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  • American Society of Hematology  (16)
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  • 1
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    Prognostic Importance of Soluble Form IL-2 Receptor á (sIL-2Rá) and Its Relationship with Surface Expression of IL-2Rá of Lymphoma Cell in Diffuse Large B-Cell Lymphoma Treated with Rituximab-Containing Chemotherapy: a Retrospective Analysis of 409 Cases.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1935-1935
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1935-1935
    Abstract: Abstract 1935 Poster Board I-958 Introduction: Several reports have identified soluble-form IL-2 receptor á (sIL-2Rá) as a significant prognostic factor in patients with non-Hodgkin lymphoma treated using chemotherapy, particularly in rituximab-containing regimens. However, the clinical significance of sIL-2R is not fully understood, as only small populations have been studied to date. The rationale for increasing of serum level of sIL-2Rá in non-Hodgkin lymphoma is also unclear. Patients and Methods: We analyzed 409 patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL) between January 2001 and July 2008. Treatment comprised CHOP-like regimen with (R-CHOP-like) or without rituximab. Levels of sIL-2R were evaluated with enzyme-linked immunosorbent assay at diagnosis. Overall survival (OS) and progression-free survival (PFS, death from any cause, relapse and refractory disease) were analyzed using Kaplan-Meier methods and survival was compared using log-rank tests. To estimate the survival impact of several factors, including sIL-2Rá level, PS, LDH, B symptoms, extranodal sites ≥2 and age, we performed multivariate analysis using Cox proportional hazards. In 166 of 409 patients, CD25 (IL-2Rá) expression on tumor cells was evaluated using a lymphoma sample from the lymph node, bone marrow, blood or other extranodal organ by flow cytometry. To estimate CD25 expression of tumor cell, CD45 bright cells (mature lymphocyte gate) were gated and considered positive if positivity was seen in 〉 20% of the population excluding CD4-positive cells) using three-color flow cytometry. Results: Median age was 68 years (range, 17-91 years), males/females 1.18, and 28.9% of patients were treated with CHOP-like regimen and 60.2% with R-CHOP-like regimen. Clinical stage was I in 24.4%, II in 24.2%, III in 13.1%, and IV in 38.8%. International Prognostic Index (IPI) was Low in 33.5%, LI in 23.5%, HI in 18.7% and H in 24.3%. Median follow-up for CHOP-like and R-CHOP-like groups was 924 days (range, 16-2878 days) and 799 days (range, 29-2688 days), respectively. Median sIL-2Rá value was 1360 U/L (range, 170-59,500 U/L). For the entire population, CR rate was 71.9%, 3-year OS was 67.6% and PFS was 58.8%. OS differed significantly between sIL-2R 〉 1000 U/L and ≤1000 U/L, between 〉 2000 U/L and ≤2000 U/L and between 〉 3500 U/L and ≤3500 U/L, (p 〈 0.001, 〈 0.001, 〈 0.001, respectively). PFS also differed at each sIL-2Rá point (p 〈 0.001, respectively). The sIL-2Rá value correlated moderately or well with other prognostic factors, such as LDH, PS ≥2, B symptoms, ≥2 extranodal lesions, age and clinical stage by Spearman correlation analysis (r=0.579, 0.258, 0.404, 0.474, respectively). Multivariate analysis showed sIL-2Rá as a significant prognostic factor, in addition to several factors. In a group treated with R-CHOP-like regimen, 3-year OS was 74.5% and PFS was 68.8%. OS again differed significantly between sIL-2Rá 〉 1000 U/L and ≤1000 U/L, between 〉 2000 U/L and ≤2000 U/L and, between 〉 3500 U/L and ≤3500 U/L (p 〈 0.001, respectively). PFS was also significant at each sIL-2Rá value. The higher the level of IL-2R, the worse the 3-year OS at each sIL-2R value (63.6%, 60.1%, 53.2%, respectively). However, we could not identify statistical significance of sIL-2 level by multivariate analysis. IL-2Rá usually functions as a cytokine receptor on cell surface, called CD25. To show the importance of CD25 expression in lymphoma cells on serum level of soluble form IL-2Rá, we compared sIL-2Rá levels in CD25-positive and -negative cases. CD25-positive cases showed significantly higher sIL-2Rá level than CD25-negative cases among the overall population. After defining two group according to clinical stage (I+II and III+IV), sIL-2Rá level was higher in the CD25-positive group than in the CD25-negative group for the stage III+IV group (p=0.001), but this difference was not seen for the stage I+II group (p=0.390). This trend was also seen in the case of IPI, L+LI (p=0.642) and HI+H (p=0.0016)). These results suggest that one rationale for increasing level of sIL-2Rá in DLBCL is removing from tumor cell like other cytokine receptor. Conclusion: In terms of survival and relapse, sIL-2R remains an important risk factor of DLBCL, not only in CHOP-like regimens, but also in the R-CHOP era. The survival rate of patients with sIL-2Rá 〉 3500 U/L is extremely poor even if treated with R-CHOP (53.2%). We showed that one rationale for increasing level of serum sIL-2Rá level in DLBCL is to remove from the tumor cell surface. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1935.1935
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
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  • 2
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    Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 5028-5028
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 5028-5028
    Abstract: Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM. Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS. Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age 〉 65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS. Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.5028.5028
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Soluble IL-2 Receptor α Is a More Sensitive Diagnostic Biomarker Than β2 Microglobulin and Predicts Survival in Follicular Lymphoma: Retrospective Analysis of 305 Cases
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3034-3034
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3034-3034
    Abstract: Introduction: Soluble-form IL-2 receptor α (sIL-2Rα) has been identified as a significant prognostic biomarker in patients with non-Hodgkin’s lymphoma (NHL) treated using rituximab-containing regimens. However, the clinical significance of sIL-2R is not fully understood, especially in subtypes of NHL, such as follicular lymphoma (FL). In addition to sIL-2Rα, β2-microglobulin (B2M) has been used as a prognostic and diagnostic biomarker of FL. We compared the predictive and diagnostic abilities of sIL-2Rα and B2M for FL. Patients and Methods: We analyzed 305 patients newly diagnosed with FL (Grade1-3a) between January 2001 and July 2012. Levels of sIL-2Rα and B2M were evaluated at diagnosis. The optimal cut-off values of sIL-2Rα and B2M were calculated from receiver operating characteristic (ROC) curves. Overall survival (OS) and progression-free survival (PFS, death from any cause, relapse and refractory disease) were analyzed using Kaplan-Meier methods and survival was compared using log-rank tests. To estimate the survival impact of several factors including sIL-2Rα, B2M, Hb 〈 12g/dl, B symptoms, LDH, bone marrow involvement, bulky disease, extranodal disease and age, we performed multivariate analysis using the Cox proportional hazards model. Results: Median age was 59 years (range: 28-86 years) and the male: female ratio was 1:1. Most (245/305) patients were treated with chemotherapy regimens. Rituximab was concomitantly administered to 227 of these patients (R-Chemo) and 52 of these patients received rituximab maintenance for 2 years. In the 305patients, clinical stage was I in 12.3%, II in 15.1%, III in 24.9%, and IV in 45.9% and the Follicular Lymphoma Prognostic Index was low in 35.7%, intermediate in 27.2% and high in 36.7%. The median follow-up period was 1,516 days (range: 7 - 4,776 days). The median sIL-2Rα value was 1,107.5 U/L (range: 127-20,800 U/L) and the median B2M value was 2.2 mg/L (range: 1.0-10.29). The 3-year OS of the entire population was 87.8% and the 3-year PFS was 65.1%. The percentage of patients whose sIL-2Rα or B2M level was higher than the upper normal limit (520 U/L for sIL-2Rα, 2.0 mg/L for B2M) at diagnosis was higher for sIL-2R (76.8%) than for B2M (54.2%) patients (p 〈 0.0001), indicating that sIL2Rα is more sensitive diagnostic marker for FL than B2M. To estimate the predictive value of sIL-2Rα and B2M for survival, we determined the optimal cut-off levels of sIL-2Rα and B2M using ROC analysis. This analysis showed that sIL-2Rα and B2M values of 1,700 U/L and 2.2mg/Lrespectivelywere the most sensitive and specific values for prediction of a 3-year PFS. Using these values, patients were separated into two significantly different groups of sIL-2Rα values ( 〉 1,700 U/L and ≤1,700 (p 〈 0.0001)) and of B2M values ( 〉 2.2 mg/L and ≤ 2.2 mg/L (p=0.0017)). Further, PFS differed significantly between patients with sIL-2Rα values of 〉 520 U/L and ≤520 U/L, 〉 1,000 U/L and ≤1,000 U/L ,and 〉 2,000 U/L and ≤2,000 U/L (p=0.03, 0.0003 and 〈 0.0001, respectively) and also between patients with B2M values of 〉 2.0 mg/L and ≤2.0 mg/L, 〉 2.5 mg/L and ≤2.5 mg/L, 〉 3.0 mg/L and ≤3.0 mg/L (p=0.011, 0.0016 and 0.0184, respectively). Univariate analysis identified several reported prognostic factors, such as clinical stage3-4, B2M 〉 2.2 mg/L, number of nodal site 〉 5, bone marrow involvement, Hb 〈 12 g/dl, performance status 〈 2, number of extranodal site 〉 1, longest diameter 〉 6 cm ( 〈 0.0001, 0.002, 0.0002, 0.0204, 0.0345, 0.0089, 0.0004 and 0.0053, respectively) in addition to sIL-2Rα (p 〈 0.0001). Cox multivariate analysis indicated sIL-2Rα as a significant prognostic factor (p=0.0361), in addition to several other factors (bone marrow involvement, number of extranodal site 〈 2, number of nodal site 〉 5). In the group treated with the R-chemo regimen, the 3-year OS was 86.9% and the 3-year PFS was 64.9%. Within this group, PFS significantly differed between the two groups of sIL-2Rα; 〉 1,700 U/L and ≤1,700 (p 〈 0.0001), and between two groups with different B2M values 〉 2.2 mg/L and ≤ 2.2 mg/L (p=0.0056). Again, multivariate analysis showed that sIL-2Rα ( 〉 1,700 U/L), in addition to several other factors, was associated with poorer prognosis. Conclusion: This study showed that sIL-2Rα is a more sensitive diagnostic biomarker of FL than B2M. In terms of survival, sIL-2R is an important risk factor of FL, not only for all patients with FL, but also in the R-Chemo era. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3034.3034
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
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    The Polymorphisms of Base Excision Repair Genes Influence the Prognosis of Multiple Myeloma
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3981-3981
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3981-3981
    Abstract: Abstract 3981 Background: The DNA in human cells is oxidatively damaged by various endogenous biochemical processes or exogenous stimuli. Base excision repair (BER) systems have important role for repairing oxidative DNA damage, and known to influence the carcinogenesis and the response to anti-cancer treatments. Although previous studies have shown that defective DNA repair is associated with an increased risk of hematologic malignancies including leukemia and lymphoma, it is unclear these polymorphisms alter the susceptibility and clinical outcome of multiple myeloma (MM) patients. The aim of this study was to evaluate the impact of polymorphisms in genes encoding four main proteins of BER system: OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His on the risk and survival of MM. Methods: We examined 93 patients [age range, 35–83 years; male/female44/49; Durie and Salmon stage I (n=8), stage II (n=22), stage III (n=61), unknown (n=2); Intenational staging system (ISS) 1 (n=21), 2 (n=21), 3 (n=29), unknown (n=22); IgG (n=55), IgA (n=15), IgD (n=2), non-secretory (n=3), Bence Jones (n=18)] with MM and 192 healthy controls. Genomic DNA was isolated from peripheral blood using the DNA extraction kit. Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Allele and genotype frequencies were calculated by direct counting. Genotype and allele frequencies were compared between patients group and control group by using Χ2-test. The characteristics and laboratory features of MM patients with each polymorphisms were compared using Χ2-tests and student t-tests. The Kaplan-Meier method was used in the calculation of overall survival (OS). Difference between the survival curves by genotypes was compared using the generalized Wilcoxon test. For the multivariate survival analyses, cox proportional hazard models were used to define the prognostic factors for OS. Probability values 〈 0.05 were considered statistically significant. All patients and healthy controls received written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital. Results: The frequencies of genotypes of BER gene polymorphism in patients with MM were as follows: Ser/Ser 35.9%, Ser/Cys 34.8%, and Cys/Cys 29.3% for OGG1; Gln/Gln 22.6%, Gln/His 49.5%, and His/His 28% for MUTYH; Arg/Arg 57%, Arg/Gln 38.7% and Gln/Gln 4.3% for XRCC1; Asp/Asp 35.5%, Asp/Glu 41.9%, and Glu/Glu 22.6% for APE1. These results showed the OGG1 Cys/Cys genotype (low DNA repair type) compared with OGG1 non-Cys/Cys genotype increases the risk of MM (OR 1.86, 95% CI 1.04–3.31, p 〈 0.05). Furthermore, the Ser/Cys genotype compared with OGG1 non-Ser/Cys genotype strongly reduces the risk of MM (OR 0.39; 95% CI 0.24–0.06, p 〈 0.0005). In contrast, there was no statistically significant difference about the risk of MM in the allele and genotype frequencies of the XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His polymorphisms between the control group and the patients with MM. When comparing OS according to APE1 Asp148Glu polymorphism, the group with APE1 Glu/Glu (low DNA repair type) showed inferior OS (median OS 3.07 years vs.5.63 years, p=0.02). In a multivariate analysis using stepwise selection, APE Glu/Glu (low DNA repair type) (p=0.02), MUTYH His/His (low DNA repair type) (p=0.0001), ISS 3 (p=0.003), and Hb 〈 10 g/dl (p=0.03) were independent prognostic factors significantly associated with shorter survival. Conclusions: According to our data, BER gene polymorphisms may affect the carcinogenesis and prognosis of MM. It is suspected that low BER activity gave rise to high DNA damage, and induced malignant transformation of plasma cell and progression to aggressive myeloma. The BER gene polymorphisms may be one of useful prognostic markers of MM and require further verification as predictive biomarkers in a larger study population. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3981.3981
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Polymorphisms of IL-10, IL-17A, IL-17F and IL-18 Affect the Clinical Features of Multiple Myeloma in Japanese Patients
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 4972-4972
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4972-4972
    Abstract: Abstract 4972 Background: The growth of plasma cells in multiple myeloma (MM) is dependent on a complex interplay among various cytokines, adhesion molecules and other factors in the tumor microenvironment. Several cytokines, including Interleukin (IL)-6, IL-10 and IL-17 have been shown to promote myeloma cell growth in vitro. Furthermore, several investigators have shown the increase in levels of serum IL-6, IL-10, IL-17, and IL-18 in MM patients compared with healthy donors. Although many studies have shown that the dysregulation of these cytokines can be associated with MM development, there are a few reports showing the influence of polymorphisms in cytokine genes on the risk of MM. We examined the single nucleotide polymorphisms (SNPs) of these cytokines: IL-10 (rs1800870 − 1082 A/G, rs1800871 − 819 T/C, and rs1800872 − 592 A/C), IL-17A (rs2275913, −197G/A), IL-17F (rs763780, 7488 T/C), and IL-18(rs187238 −137G/C and rs1946518 −607 A/C) in MM patients, and analyzed the relationship between these SNPs and the susceptibility and clinical features. Patients and Methods: Ninety three patients [age range, 35–83 years; male/female 44/49; Durie and Salmon stage I (n=8), stage II (n=22), stage III (n=61), unknown (n=2); International staging system (ISS) 1 (n=21), 2 (n=21), 3 (n=29), unknown (n=22); IgG (n=55), IgA (n=15), IgD (n=2), non-secretory(n=3), Bence Jones(n=18)] with MM and 192 healthy race- and sex-matched healthy controls were examined. Genomic DNA was isolated from peripheral blood using the DNA extraction Kit. Genotyping of IL-10, IL-17A, and IL-17F polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the genotyping of the IL-18 polymorphism was determined by the allelic specific polymerase chain reaction technique. Genotype and allele frequencies were compared between the study groups using Χ2-test. The characteristics and laboratory features of MM patients with each polymorphisms were compared using Χ2-tests and student t-tests. The Kaplan-Meier method was used in the calculation of overall survival (OS). OS were compared with the log-rank test. Probability values 〈 0. 05 were considered statistically significant. Results: Genotype and allele frequencies of cytokines in MM patients and the control: The frequencies of genotypes of cytokines in patients with MM were as follows: AA 92. 5% and AG 7. 5% for IL-10–1082; TT 43%, TC 48. 4% and CC 8. 6% for IL-10–819; AA 43%, AC 48. 4% and CC 8. 6% for IL-10–592; AA 19. 4%, AG 40. 9% and GG 39. 8% for IL-17A-197; TT 82. 8% and TC 17. 2% for IL-17F; GG 65. 6%, GC 26. 9% and CC 7. 5% for IL-18–137; AA 35. 5%, AC 47. 3% and CC 17. 2% for IL-18–607 loci. No significant differences were observed in the allele or genotype frequencies of IL-10 and IL-17F polymorphisms between MM patients and the control group. However, patients with MM had a significantly higher frequency of the IL-18–137 CC genotype compared to the control group (7. 5% vs. 2. 2%, P 〈 0. 05). The number of IL-18–137 C alleles among the patients with MM was also higher than in the control group (21% vs. 13. 3%, p 〈 0. 05). Furthermore, MM patients had a significantly lower frequency of the IL-17A A/G genotype compared to the control group (40. 9% vs. 58. 7%, P 〈 0. 01). Patients' characteristics according to cytokine polymorphisms: IL-10 592 CC genotype (high producer type) was significantly associated with advanced ISS (P=0. 03) and higher β2 microglobulin level (CC vs non CC; 9. 81±4. 78 g/dL vs. 5. 27±3. 27g/dL, p 〈 0. 05). IL-17A-197 AA genotype (high producer type) was also significantly associated with higher bone scale (66. 6% vs 44%, p=0. 05). IL-18–137 CC or GC genotype was significantly associated with advanced ISS (P 〈 0. 05) and lower hemoglobin level (8. 8±2. 6 mg/dL vs. 9. 9±2. 4 mg/dL, p=0. 04). Although there was no significant difference in overall survival of IL17 A, IL-17F and IL-18 polymorphisms, patients with IL-10–592 CC or IL-18–607 AA genotype showedtendency to more unfavorable survival (p=0. 07). A multivariate analysis using cox proportional hazard model demonstrated that Bence Jones protein (p=0. 001), ISS stage III (p 〈 0. 05), the use of new drugs (p=0. 001), IL-10–592CC genotype (P=0. 005) and IL-17 AA (P=0. 00001) were independent adverse prognostic factors. Conclusion: These results indicate that cytokine polymorphisms, including IL-10, IL-17 and IL-18, are associated with prevalence and clinical feature of MM in Japanese patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.4972.4972
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 6
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    Common Fragile Site Gene FRA16D WWOX (WW domain containing oxidoreductase) Is Frequently Altered in Plasma Cells of Multiple Myeloma and MGUS, Possibly Related to Disease Development
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4646-4646
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4646-4646
    Abstract: Abstract 4646 The common fragile sites (CFSs) are regions of profound genomic instability, and hot-spots for deletions and other alterations in cancer cells. We have previously shown that promoter of FHIT is frequently methylated in multiple myeloma (MM) and correlated with worse prognosis. WWOX is located at a CFS region on chromosome 16q23.3, this gene is also a target of alterations in multiple cancers. The objective of current study is to find if this tumor suppressor gene is altered in MM and MGUS. Six myeloma cell lines, bone marrow mononuclear cells (BMMNC) of 165 MM and 25 MGUS patients were subjected to this study after obtaining informed consent. Isolated CD138 positive plasma cells (PC) of 24 MM were examined to see if the alteration occurred really in myeloma cells. Using methylation specific PCR, WWOX promoter methylation was detected in 2 of 6 cell lines, 35% of MM patients and 8% of MGUS patients (p=0.01). The overall survival of the MM patients with methylated WWOX tended to be worse than with unmethylated WWOX (p=0.2). Using nested RT-PCR, aberrant short transcripts of WWOX lacking exons coding SDR domain were detected in 4 cell lines, 68% of MM and 60% of MGUS (p=0.51) In isolated PC, aberrant transcripts of WWOX were detected in 58% of MM and 25% of MGUS (p=0.02). Real time PCR demonstrated higher WWOX expression in isolated PC of MM and MGUS than of BMMNC other than plasma cells (p=0.0001), and those higher WWOX were aberrant type (p=0.001). As aberrant WWOX is known to function as dominant negative for wild type, our results imply that this aberrant WWOX is an oncogene as well as losing tumor suppressor function. Since WWOX is demonstrated to regulate beta-catenin and NF-kB pathway, high frequency of aberrant WWOX expression indicates an important role in myeloma development. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4646.4646
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
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    Innate Immunity in Idiopathic Thrombocytopenic Purpura (ITP)
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 4907-4907
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4907-4907
    Abstract: Background: Dendritic cells (DCs), natural killer (NK) cells, and invariant NKT (iNKT) cells play important roles in innate immune systems. These cells have recently been shown to be involved in immunoregulation, and some studies have suggested associations with various kinds of autoimmune disease. Conversely, regulatory T cells (Tregs) that are important for peripheral tolerance and Th17 cells that play a central role in maintenance of chronic inflammation are also associated with the pathogenesis of several autoimmune diseases. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies, but relationships to innate immunity are unclear. In addition, the pathogenesis of ITP associated with Helicobacter pylori remains obscure. In particular, the regulation of immune responses by these cells in patients infected with H. pylori has not been investigated. This study analyzed DCs, NK cells, iNKT cells, Tregs and Th17 cells in patients with ITP. Methods: Subjects comprised 31 patients with ITP and 22 healthy donors. Study protocols were approved by the Institutional Review Board of Gunma University Hospital, and written informed consent was obtained from all subjects. Flow cytometry was used to investigate amounts of circulating plasmacytoid DCs (pDCs) (CD123+ HLA−DR+) and myeloid DCs (mDCs) (CD11c+ HLA−DR+) from whole white blood cells, and NK cells (CD3− CD56+), iNKT cells (Vα24+ Vβ11+), Tregs (CD4+ CD25+ Foxp3+) and Th17 cells (CD4+ IL−17A+) from mononuclear cells. The intracellular interleukin (IL)-17A production in CD4+ T-cells activated by phorbol 12-myristate 13-acetate (PMA) and ionomycin was assessed to detect Th17 cells. Results: Both the percentage and numbers of pDCs were significantly reduced in patients compared to healthy controls (p & lt;0.001), while those of mDCs tended to be lower in patients than in controls, but with no significant differences. NK cell counts tended to be higher in patients than in controls and counts of iNKT cells tended to be lower in patients than in controls, but again no significant differences were demonstrated. Notably, Treg levels were comparable between patients and controls, while Th17 cells were significantly increased in patients compared with controls (p & lt;0.002). In all cases, no significant differences were demonstrated between patients with H. pylori-positive and -negative results. Conclusion: These results suggest that alterations in innate immunity as a reduction of pDCs could be associated with the pathogenesis of ITP. Furthermore, as in some autoimmune diseases that have been considered as Th1 diseases, Th17 cells may play an important role in ITP.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.4907.4907
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Impact Of Sex On Clinical Outcomes Of Mature B Cell Lymphoma In The Rituximab Era: A Multicenter, Retrospective Study
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 5056-5056
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5056-5056
    Abstract: Rituximab has dramatically improved the clinical outcomes of mature B cell lymphoma. It has been reported that women show more favorable survival than men with rituximab-containing treatment. A multicenter, retrospective study was conducted to assess the role of sex in survival with rituximab treatment. Patients and Methods Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals in Japan from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The target population of this study was all mature B cell lymphoma patients who received first remission induction therapy containing rituximab. The patients treated without rituximab were used as controls. The endpoint was to compare 2-year progression-free survival (PFS) and overall survival (OS) between men and women. Survivals were assessed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Results A total of 1126 patients received systemic chemotherapies during this study period. Of these, 348 (men 185, women 163), including 184 diffuse large B cell lymphomas (DLBCLs) and 111 follicular lymphomas (FLs), were treated by rituximab-containing regimens as front-line therapy. The 2-year PFS was better in women than in men (75.8% vs. 64.2%, p=0.048). This difference was not seen in the control group (men 396, women 382), which was treated by chemotherapeutic regimens without rituximab (48.7% vs. 50.6%, p=0.994). The 2-year OS was not statistically different between men and women (81.9% vs. 88.6%, p=0.115). When this population was broken down into DLBCL and FL, the women’s benefit in 2 year PFS was not statistically significant in both subtypes. Multivariate analysis both with forced entry and stepwise method could not show that sex was an independent prognostic factor in mature B cell lymphoma treated by rituximab containing induction regimen. Conclusions In mature B cell lymphoma, women would have better PFS than men when treated with rituximab containing therapy. These data suggest that the sex-based rituximab dose modification might be considered. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.5056.5056
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 9
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    Significantly Reduced Circulating Plasmacytoid Dendritic Cells In Patients with Primary and Helicobacter Pylori-Associated Immune Thrombocytopenia
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2531-2531
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2531-2531
    Abstract: Abstract 2531 Background: Immune thrombocytopenia (ITP) is an autoimmune disorder caused by production of autoreactive antibodies against platelet antigens. The association between Helicobacter pylori infection and a subgroup of ITP is now widely recognized. Although multiple dysfunctions in cellular immunity are considered to be important in the pathogenesis of ITP, little is known about the role of innate immune cells. Dendritic cells (DCs) play an essential role in innate and adaptive immune response by regulating the differentiation of naïve T cells and interacting with NK or NKT cells. DCs are composed of two subsets: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in human peripheral blood. PDCs play an important role in several autoimmune diseases such as systemic lupus erythematosus through their ability to produce large amounts of type I interferon. In the present study, we analyzed the number of circulating DCs, regulatory T (Treg) cells, Th17 cells, NK cells and NKT cells in untreated patients with primary and H. pylori-associated ITP and assessed the changes of DC subsets after treatment in order to elucidate the role of these cells in the pathogenesis of ITP. Methods: This study was approved by the local institutional review board. After obtaining written informed consent, we enrolled 46 untreated patients with chronic ITP (38 females and 8 males; median age: 52.5 years) and 47 healthy adult volunteers (43 females and 4 males; median age: 50.5 years). We investigated the percentage and the absolute number of circulating pDCs (Lineage marker (Lin)− CD123+ HLA-DR+) and mDCs (Lin− CD11c+ HLA-DR+) in whole blood, and NK cells (CD3− CD56+), invariant NKT (iNKT) cells (Vα24+ Vβ11+), Treg cells (CD4+ CD25+ Foxp3+) and Th17 cells (CD4+ Interleukin (IL)-17A+) among peripheral blood mononuclear cells (PBMCs) by flow cytometry. Intracellular IL-17A production in CD4+ T cells activated by phorbol 12-myristate 13-acetate (PMA) and ionomycin was assessed in order to detect Th17 cells. In addition, we consecutively analyzed the number of DC subsets in ITP patients before and after H. pylori eradication or the administration of prednisolone (PSL). Results: H. pylori was detected in 15 of 38 patients (39.5%), and 7 of 15 H. pylori-positive patients (46.7%) probably had secondary ITP (H. pylori-associated), as platelet count elevation was observed only after H. pylori eradication in these cases. Thirteen patients underwent H. pylori eradication and 9 patients underwent PSL. We found a significant reduction in the percentage and absolute number of pDCs in untreated ITP patients when compared with controls (p 〈 0.001), while the percentage and absolute number of mDCs tended to decrease in ITP patients; however, the differences were not significant. In addition, the frequency of circulating pDCs was significantly lower in H. pylori-positive patients when compared with controls (p 〈 0.05) and was equal to that in H. pylori-negative patients. The frequency of circulating Treg cells, Th17 cells, NK cells and iNKT cells in ITP patients was similar to that in controls. Interestingly, we observed increases in the frequency of pDCs after H. pylori eradication only in responders, while there were no changes or slight reductions after this treatment in non-responders. On the other hand, we were unable to elucidate the relationship between changes in the frequency of mDCs and H. pylori eradication. To investigate the differences with treatment type, we performed serial measurement of DC numbers in cases treated by oral administration of PSL, which is standard therapy in primary ITP patients. The frequency of both pDCs and mDCs in all cases treated with PSL was markedly reduced in 1–2 months after treatment and tended to increase with dose reduction for 3–8 months after treatment. Because there were no differences in this trend between responders and non-responders to PSL, and because the frequency of DC subsets appeared to be inversely correlated with PSL dose, we considered that these results were caused by PSL, in contrast to cases undergoing H. pylori eradication. Conclusion: We found for the first time that circulating pDCs were significantly reduced in untreated patients with both primary and H. pylori-associated ITP. In addition, the reduced number of pDCs was restored after eradication in H. pylori-associated ITP patients. This suggests that pDCs play an important role in the pathogenesis of ITP. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2531.2531
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 10
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    Survival of Multiple Myeloma Patients in the Era of Novel Agents and Autologous Stem Cell Transplantation: A Multicenter Retrospective Collaborative Study of the Japanese Society of Myeloma
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 5684-5684
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5684-5684
    Abstract: Introduction A significant progress in the management of multiple myeloma (MM) has been made in recent years by the introduction of novel treatment modalities including high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) and novel drugs such as proteasome inhibitors and immunomodulatory drugs (IMiDs). Nevertheless, MM is still an incurable disease with various complications, and it is not clear whether these approaches contribute to the improvement of patient outcomes in routine practice. Previously, the Japanese Society of Myeloma surveyed the clinical features of 1383 patients with MM diagnosed and treated between January 1990 and December 2000. In the present study, we conducted a multicenter retrospective study to evaluate the treatment outcome and prognostic factors in the era of novel agents in Japan involving 2593 new patients diagnosed and treated after December 2000. Patients and Methods We analyzed 2593 patients with symptomatic MM newly diagnosed in the period between January 2001 and December 2012 at the affiliated hospitals of the Japanese Society of Myeloma. This study was conducted in accordance with the institutional guidelines with approval of the local institutional review board. There were 1342 males and 1251 females. The median age was 66 (range 26-96) years; 21% were older than 75 years. The type of monoclonal immunoglobulin was IgG in 1547 patients, IgA in 488, light chain only in 399, IgD in 72, and others in 87, respectively. Performance status (PS) of 0, 1, ≥2, and unknown were 340, 657, 756, and 840 patients, respectively. Durie & Salmon stage was as follows: 8.4% had Stage I, 25.5% Stage II, and 66.1% Stage III, respectively. As for the International Staging System (ISS) stages, 28.0% had stage I, 38.0% stage II, and 34.0% stage III, respectively. Cytogenetic abnormalities were detected in 24.9% of the patients. Initial therapy was composed of conventional chemotherapy in 45.6%, novel agents such as bortezomib-based or IMiDs-based regimens in 20.6%, conventional chemotherapy + ASCT in 20.4%, and novel agents (mainly bortezomib) + ASCT in 12.8% of the patients, respectively. Results The median overall survival (OS) was 63.8 and 62.5 months in the 2001-2005 cohort and in the 2006-2012 cohort, respectively, which was significantly improved compared with our previous results of 38.9 months in the 1990-2000 cohort. The median OS tended to be shorter according to the patient age (97.3, 79.7, 56.9, and 44.6 months in the patients aged 〈 50, 50-64, 65-74, and ≥75 years, respectively). When we compared the outcome in the 2001-2005 cohort and that in the 2006-2012 cohort, the extended OS was observed only among the younger patients ( 〈 75 years). As for the disease stage, Durie & Salmon stage III and ISS stage III were strongly associated with inferior OS. Cytogenetic abnormalities were also associated with inferior OS. In terms of initial therapy, the median OS were 46.6, 62.9, 96.5, and 91.0 months for the conventional chemotherapy group, novel agent-containing regimen group, conventional chemotherapy + ASCT group, and novel agents + ASCT group, respectively (p 〈 0.0001). Our previous results of the 1990-2000 cohort showed that the median OS were 37.1 and 64.8 months in the conventional chemotherapy group and conventional chemotherapy + ASCT group, respectively (p 〈 0.0001). Thus, a significant improvement was observed in the novel agent group and ASCT group among the current cohort. In a multivariate analysis, age (p=0.0004), Durie & Salmon stage III (p=0.0001), ISS stage III (p 〈 0.0001), and cytogenetic abnormality (p 〈 0.0001) were independent prognostic factors significantly associated with inferior OS, and novel agent-based therapy (p 〈 0.0001) and ASCT (p=0.013) as initial therapy were significant favorable factors for OS. Conclusion In comparison with our previous survey, the current study confirmed the recent improvement of the treatment outcome and the impact of both novel agents and ASCT as initial therapy on the outcome. The use of novel agents as salvage therapy could have also provided additional survival benefit. However, the prognosis of elderly patients remains unaltered, and alternative approaches are needed to improve the outcome of elderly patients with MM. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.5684.5684
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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