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  • 1
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    JAK2 Mutation Status in Granulocytes, Platelets and Erythrocytes Differs Between Polycythemia Vera and Essential Thrombocythemia
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 5228-5228
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 5228-5228
    Abstract: Background The gain-of-function point mutation in Janus kinase 2 exon 14 gene (JAK2-V617F) influences the diagnosis of bcr/abl-negative chronic myeloproliferative disorders (CMPDs). We previously reported that analyzing platelets is advantageous in detecting the JAK2-V617F mutation, particularly in essential thrombocythemia (ET), when compared to granulocytes. However, there have been few reports analyzing the JAK2-V617F mutation in erythroid lineage cells, and comparing the mutation status in all three lineages. Method Study protocols were approved by the Institutional Review Board of Gunma University Hospital, and written informed consent was obtained from all the patients. Heparinized peripheral blood was obtained from 113 patients with CMPDs (82 with ET, 25 with polycythemia vera (PV), and 6 with primary myelofibrosis (PMF). After centrifugation, platelets were collected from the upper plasma layer. Remaining blood was mixed with Hank’s Balanced Salt Solution and was subjected to Ficoll-Hypaque density gradient centrifugation. Granulocytes were obtained from the pellet. Mononuclear cells were resuspended in RPMI 1640 medium; 5 × 105 cells were plated in duplicate in 1 ml of methylcellulose medium and cultured in a humidified atmosphere of 5 % of carbon dioxide at 37°C for 14 days in the presence of erythropoietin to obtain erythroid colonies (BFU-E). T-cells were obtained from the remaining mononuclear cells using anti-CD3 immunoconjugated magnetic beads. After extraction of DNA from granulocytes, T-cells and BFU-E, and RNA extraction from granulocytes and platelets, PCR amplification and sequencing of exon 14 of the Jak2 gene was performed to confirm the presence of JAK2-V617F mutations. To confirm the mutation status of granulocytes, T-cells and BFU-E, allele-specific PCR (AS-PCR) was performed. Results For ET, 57 out of 82 patients (69.5%) had the JAK2-V617F mutation. In the 57 patients with the JAK2-V617F mutation, 38 (67%) had the mutation in all three lineages, 5 had the mutation in granulocytes and platelets, 2 had the mutation in platelets and BFU-E, 10 patients had the mutation only in platelets and 2 patients had the mutation only in BFU-E. In contrast, for PV, 22/25 patients (88%) had the JAK2-V617F mutation. Of note, in 22 patients having JAK2-V617F mutation, 20 (91%) were JAK2-V617F mutation-positive in all three lineages; the remaining two patients had the mutation in either platelets or BFU-E. The frequency of JAK2-V617F in all three lineages was significantly higher in PV than in ET (p & lt; 0.05). For PMF, 5 of 6 patients had the mutation in granulocytes, and 3 of these had it in all three lineages. Conclusion Among JAK2-V617F mutation-positive CMPDs, most PV patients had the JAK2-V617F mutation in all three lineages, thus suggesting that the JAK2-V617F mutation occurs in progenitor cell(s) common to granulocytes, platelets and erythrocytes. In contrast, only 67% of ET patients had the JAK2-V617F mutation in three lineages; in the remaining cases, not all of the three lineages have the mutation. This difference in lineages showing the JAK2-V617F mutation between the ET and PV may be related to the pathophysiological differences in ET and PV. Furthermore, the heterogeneous mutation status in ET may be related to its heterogeneous clinical manifestation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.5228.5228
    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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  • 2
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    HLA-DRB1 Analysis in Hairy B-Cell Lymphoproliferative Disorder (HBLD): A Japanese Type of Benign Persistent Polyclonal B-Cell Lymphocytosis.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4417-4417
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4417-4417
    Abstract: Two types of benign persistent polyclonal B-cell Lymphocytosis have been reported: persistent polyclonal B-cell lymphocytosis (PPBL) in Western countries and hairy B-cell lymphoproliferative disorder (HBLD) in Japan. PPBL is characterized by B lymphocytosis with binucleated lymphocytes, polyclonal IgM, isolated splenomegaly, female sex, cigarette smoking and the presence of HLA-DR7 allele. Most patients with HBLD have atypical lymphocytes with microvilli and prominent membranous ruffles, serum polyclonal IgG, and splenomegaly. Only 9 patients with HBLD have been reported to date, and all of these patients are Japanese. Here, we report three new cases of HBLD. We performed HLA-DRB1 subtyping since the association between HBLD and HLA-DR4 has been suggested: 4 of 5 HBLD patients examined demonstrated the HLA allele. We also analyzed HLA-DRB1 alleles in a patient with hairy cell leukemia (HCL) and 3 with HCL Japanese variant (HCL-JV) to examine the possibility that polyclonal cell expansion in HBLD may be followed by transformation to these lymphoproliferative disorders. If the transformation were to occur, the patients should share the same HLA-DR allele. Expanded B-lymphocytes in all HBLD cases displayed CD5− CD10− CD11c+ CD19+ CD20+ CD23− CD25− and CD103− cell surface phenotype and all patients exhibited a polyclonal increase in serum IgG. Phase-contrast microscopic and scanning electron microscopic examinations demonstrated lymphoid cells with many long surface microvilli. Analysis of immunoglobulin VH gene rearrangements showed a polyclonal pattern. Therefore, we diagnosed these patients as HBLD. HLA-DRB1 subtype analysis strengthened the close relation between HBLD and HLA-DR4: 2 patients having HLA-DRB1*0405 and one HLA-DRB1*0407. In the meanwhile one each patient with HCL and HCL-JV had HLA-DRB1*0405 allele. Although the exact mechanism underlying the association between HBLD and HLAB1*04 needs to be elucidated, the presence of this HLA might be useful to establish correct diagnosis of the disease, and thus avoid patient exposure to unnecessary treatment. One each patient with HCL and HCL-JV has HLA-DRB1*0405, but a definitive conclusion cannot yet be drawn due to high HLA-DRB1*04 frequency in Japanese population (25.4%).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4417.4417
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 3
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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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  • 4
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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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  • 5
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    Interleukin-10 Gene Polymorphism Reflects the Severity of Chronic Idiopathic Thrombocytopenic Purpura.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2111-2111
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2111-2111
    Abstract: Introduction: Recent several cytokine studies have shown Th1 polarization of the immune response in Idiopathic thrombocytopenic purpura (ITP) patients. IL–10 is most important factor regulating Th1 and Th2 cytokine synthesis and IL–10 polymorphism has been implicated in autoimmunity and tumorigenesis. We examined the single nucleotide polymorphisms (SNPs) in the promoter regions of the IL–10 genes in patients with ITP, and analyzed the relationship between IL–10 SNPs and clinical features. Patients and methods: Seventy-eight patients (male/female; 19/59, median age; 59.4) diagnosed as chronic ITP and 202 healthy controls were included. ITP with severe thrombocytopenia was defined as thrombocytopenia (platelet count & lt; 10×109/L) at initial diagnosis of ITP. ALL patients gave written informed consent about the study. The platelet count was ranged from 1×109/L to 100×109/L at an initial diagnosis. In addition, 53 patients (67.9%) had bleeding tendency, and 20 patients (25.6%) had severe thrombocytopenia. Steroid treatment was given to 48 patients (61.5%), while splenectomy was applied to only 9 patients (11.5%). Genotyping in IL-10-1082G/A, -819C/T, −592A/C was determined by PCR based technique. Genotype and allele frequencies were compared between the study groups using χ2-test. The characteristics and laboratory features of the ITP patients with each IL-10 promoter polymorphism were compared using X2-tests and student t-tests. Probability values & lt;0.05 were considered statistically significant. Results: The frequencies of the genotypes were as follows: GG (0%), GA (6%), and AA (94%) for −1082; CC (12%), CT (51%), and TT (37%) for −812; CC (12%), CA (51%), and AA (37%) for −592 loci. The frequencies of each haplotype were as follows: ATA/ATA haplotype in 31 patients (40%), ATA/ACC haplotype in 35 patients (45%), ACC/ACC haplotype in 7 patients (9%). No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control group. However, patients with −592AA genotypes showed severe thrombocytopenic state at initial diagnosis compared to those with −592CA/CC genotypes (41.4% vs. 16.3%, p=0.01). Furthermore, patients with ATA/ATA haplotype showed severe thrombocytopenic state (38.7% vs. 17%, p=0.03) compared to those without ATA/ATA haplotype. In patients treated with steroids, the overall response rate was 71% with complete response rate of 23.2% and partial response rate of 47.8%. No significant difference was observed in treatment response according to IL-10 polymorphism. Conclusion: In previous investigations, −592AA genotype or ATA/ATA haplotype have been reported to be associated with the lower levels of IL-10 expression. Our data suggest that the group with low IL-10 inducibility (i.e. −592AA genotype, ATA/ATA haplotype) may have more severe thrombocytopenia compared to those with high IL-10 inducibility. It is also reported that low IL-10 inducibility type enhances Th1-type polarization in ITP. Furthermore, Panitsas et al. revealed that higher Th1/Th2 ratio in ITP patients correlate with lower platelet count. Thus, these findings suggest that IL-10 polymorphism reflect the severity of chronic ITP.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2111.2111
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 6
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    Risk Factors for Central Nervous System (CNS) Relapse after Autologous Stem Cell Transplant (ASCT) in Diffuse Large B-Cell Lymphoma (DLBCL)
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5344-5344
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5344-5344
    Abstract: Background:Although the addition of rituximab to CHOP regimen improved prognosis in DLBCL patients with more than 80% of a long-term survival rate, CNS relapse did not decrease and 5 to 10% of patients experienced CNS relapse after rituximab-containing chemotherapy. Risk factors for CNS relapse after standard chemotherapy have been aggressively investigated, and a risk model, CNS-international prognostic index (IPI), has been widely used. However, risk factors for CNS relapse after high-dose chemotherapy following ASCT, which is recognized as an important treatment option for high-risk DLBCL patients, have not been elucidated. So, we performed this retrospective analysis to address this unsolved issue. Patients and methods:This study analyzed 87 adult patients who underwent ASCT against chemo-sensitive DLBCL including intravascular large B-cell lymphoma (IVLBCL) between 1997 and 2015 at the four institutions in Gunma, Japan. There was no restriction on the type of conditioning regimens. CNS-directed regimens were defined as chemotherapy or conditioning regimens containing high dose cytarabin, high dose methotrexate, busulfan, ranimustine, or total body irradiation. Only the first relapse after ASCT was assessed in this study. Fisher's exact test was used to compare binary variables. Cumulative incidences (CIs) of CNS relapse were compared using the stratified Gray test, considering relapse without CNS lesions and death without the event as a competing risk. The Fine-Gray proportional hazard model was used for multivariate analysis of risk factors for CNS relapse. The potential risk factors evaluated in this analysis were age at transplant, gender, clinical stage, IPI (high-intermediate/high or not), and CNS-IPI (high or not) at diagnosis, CD5 positivity, CNS involvement prior to ASCT, CNS-directed chemotherapy prior to ASCT, and CNS-directed conditioning regimen. Values of p 〈 0.05 were considered significant. Results:Of the 87 patients assessed in this study, 48 were male and 39 were female, and the median age was 57 years (range: 23 to 66 years). CD5 was expressed in 19% of the patients, and 10% were diagnosed as IVLBCL. CNS-IPI at diagnosis was high in 53%, and rituximab and CNS-directed chemotherapy was administered prior to ASCT in 83% and 16%, respectively. CNS involvement was observed prior to ASCT and at the time of ASCT in 9% and 0%, respectively. Disease status at the time of transplant was first complete remission (CR) in 47%, advanced CR in 23%, and partial remission in 30%. CNS-directed conditioning regimens were used in 38%. With a median observation time of 21.9 months, seven patients experienced CNS relapse as the first relapse after ASCT. The 3-year CI of CNS relapse was 7.3% with 5.7 months of median duration from ASCT (range: 2.7 to 69.0 months). In univariate analysis, only CD5 positivity was identified as a significant risk factor for CNS relapse (3-year CIs in patients with and without CD5 expression: 27.0% vs. 2.2%, respectively; p 〈 0.01). In multivariate analysis, CD5 positivity, CNS-IPI at diagnosis, CNS-directed chemotherapy prior to ASCT, and CNS-directed conditioning regimen were evaluated, and only CD5 positivity was identified as an independent risk factor for CNS relapse (relative risk=20.1; p 〈 0.01). Of the seven patients with CNS relapse after ASCT, four expressed CD5 and five received CNS-directed chemotherapy prior to ASCT and/or conditioning regimens. All seven patients died from DLBCL within two years after CNS relapse. Conclusion:These results suggested that CNS relapse occurred in DLBCL patients even after ASCT with similar incidence to that after chemotherapy. Although prophylactic strategies for CNS relapse should be investigated especially in patients with CD5-positive patients, use of CNS-directed chemotherapy prior to ASCT and/or conditioning regimens did not affect the CIs of CNS relapse. A future study with a larger cohort is warranted to develop a risk model for CNS relapse after ASCT in DLBCL patients. Disclosures Handa: Ono: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-127990
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 7
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    Matrix Metalloproteinase and Tissue Inhibitor of Metalloproteinases Is Associated with Multiple Myeloma Progression, Prognosis and Extramedullary Plasmacytoma
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3178-3178
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3178-3178
    Abstract: Backgrounds and Aims: Matrix metalloproteinase (MMP) is endopeptidase enzyme degrading extracellular matrix, and tissue inhibitor of metalloproteinases (TIMP) is negative regulator of MMP. MMP is well known to be involved in metastatic mechanism of cancer cell and oncogenesis. However expression and role of MMP and TIMP has not been well established in multiple myeloma (MM). Therefore we examined whether expression of MMP and TIMP was involved in progression and prognosis of MM and extramedullary plasmacytoma (EMP) formation. Materials and Methods: Purified bone marrow plasma cells by using anti-CD138 antibody and magnetic beads obtained from 151 MM, 64 MGUS, 18 control and 5 EMP were subjected to the study after informed consent. The study was approved by IRB following Declaration of Helsinki. Whole transcriptome by next generation sequencer (NGS) using Illumina Next Seq 500 was performed in part of the samples to select genes to be studied, then expression level of MMP and TIMP determined by RQ-PCR Delta Ct value normalized with ACTB was used for analysis. MM cell lines KMS11, KMS12PE, KMS12BM, KMM1, RPMI8226, MM1S were used for the in vitro study. Results: We selected TIMP-1, 2and MMP14, 24 based on transcriptome analysis data comparing MM and EMP. The expression level of TIMP1 and MMP24 was significantly higher in MM (median delta Ct: 0.033 for TIMP1, 0.00025 for MMP24) than in MGUS (median delta Ct: 0.013 for TIMP1, 0.00006 for MMP24) (p=0.005, p=0.001), however TIMP2, MMP14 level did not differ in between MM and MGUS. Interestingly, TIMP1, 2 and MMP14, MMP24 were expressed with strikingly higher levels in EMP than in MM with 20 times, 60 times, 300 times, 500 times respectively (p=0.01, p=0.02, p=0.004, p=0.004). Both TIMP1 and 2 expression were higher in the MM patients with high risk cytogenetic karyotype t(4;14), t(14;16), del 17p than in the patients without such karyotype (p=0.006, p=0.008), however the levels of MMP14 and 24 did not differ in between cytogenetic risk groups. Positive correlations were found in between TIMP1 and 2, MMP14 and 24 in both MM and MGUS group respectively (r=0.34, p 〈 0.001, r=0.49, p 〈 0.001 in MM, r=0.32, p=0.008, r=0.63, p 〈 0.001 in MGUS). Since TIMP2 and MMP14 were higher in EMP, the effect of recombinant TIMP2, siRNA-TIMP2 and MMP14 inhibitors marimastat/ilomastat were tested in MM cell lines KMM1, KMS11, KMS12PE and RPMI8226. However, these interventions did not change proliferation rates of these cell lines. The cell lines were treated with doxorubicin or bortezomib to study if these agent can change TIMP and MMP expression. Doxorubicin significantly increased expression level of MMP14, 24 and TIMP1, 2, but bortezomib increased only MMP14, 24. In the newly diagnosed MM (NDMM) patients (n=77), median time of overall survival (OS) of the patients with high TIMP1 (more than median value) was significantly shorter (2.7 years vs not reached) and 3 year OS rate was inferior (40% vs 65%) (p=0.0095). Progression free survival (PFS) tended to be inferior for high TIMP1 group, but the difference did not reach statistical significance (p=0.221). OS and PFS were not different according to either TIMP2, MMP14 or MMP24. Conclusions: Our results suggest that TIMP1, 2 and MMP14, 24 were associated with EMP formation. Among those factors, TIMP1 is the one which may play a key role for MM progression and chemo-resistance based on the results revealing its upregulation by antineoplastic agents and association with poor prognosis of MM patients. Our results is consistent with a previous report describing that high serum TIMP1 concentration was associated with poor prognosis of MM. TIMP is recently shown to play another role besides negative regulator for MMP, so further study to elucidate its specific role for chemo-resistance contributes to develop novel therapy targeting TIMP and MMP pathway. Disclosures Tsukamoto: Kyowa-Kirin: Research Funding; Chugai: Research Funding; Eisai: Research Funding; Pfizer: Research Funding. Handa:Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-113355
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 8
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    Clinical Significance of Clonal Cytogenetic Heterogeneity (CCH) at Diagnosis in Adult Patients with Acute Lymphoblastic Leukemia (ALL)
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2820-2820
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2820-2820
    Abstract: Background:Although cytogenetic abnormalities at diagnosis are recognized as one of the most potent prognostic factors in acute leukemia patients, CCH acquisition at diagnosis, which are considered as a result of clonal evolution of leukemia cells, is not taken into account in prognostic classifications. Recent studies reported that CCH acquisition was observed in 24 - 32% of adult AML patients with abnormal karyotype, was more likely to occur in patients with older age and complex karyotype, and showed adverse prognostic impact. However, the clinical significance of CCH acquisition has not been investigated in adult ALL patients to date. Patients and methods: Of the 238 adult ALL patients diagnosed between 1990 and 2016, 120 patients with abnormal karyotype at diagnosis, who underwent intensive chemotherapy, were included in this study. CCH was defined as presence of two or more cytogenetically abnormal clones. A defined ancestral clonal evolution included either mother-daughter and/or branched patterns. In the mother-daughter pattern, a daughter clone showed all cytogenetic abnormalities of a mother clone plus additional abnormality(s), which define a distinct subclone. In a branch pattern, all subclones possessed common cytogenetic abnormalities suggesting presence of a common ancestry, but each subclone acquires unique additional abnormality(s), which define them as distinctive subclones. Both patterns of cytogenetic clonal evolution were sometimes seen in a patient. Composite karyotypes were applied to patients where a common ancestry could not be clearly determined because of too complicated cytogenetic findings. Fisher's exact test was used to compare binary variables. The logistic regression model was used for multivariate analysis of predisposing factors. Overall survival (OS) was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. Values of p 〈 0.05 were considered to indicate statistical significance. Results:Of the 120 patients included in this study, 64 patients were male, and 56 were female. The median age was 50 years (range, 16-79 years). Karyotypes at diagnosis were Philadelphia chromosome (Ph) in 56 patients, complex in 15, and t(8;14) in seven. According to the definition described above, 47 patients (39%) showed CCH at diagnosis, and two (4%) among them were categorized as composite karyotype. Of the 45 patients harboring a defined ancestral clonal evolution, numbers of subclones were two, three, and four in 32 patients (68%), 11 (24%), and 2 (4%), respectively. Mother-daughter pattern, branched pattern, and both were seen in 34 patients (76%), 5 (11%), and 6 (13%). In univariate analysis for predisposing factors of CCH acquisition, only younger age was significantly associated with CCH acquisition (48% in age 〈 = 50 vs. 29% in age 〉 50; p = 0.04), but not karyotype. This statistical significance was confirmed with multivariate analysis (odds ratio = 0.44; p = 0.03). When investigating the prognostic impact of CCH acquisition, patients were divided into Ph-negative or Ph-positive ALL groups. In the 64 Ph-negative ALL patients, the CR rates were not significantly different between patients with or without CCH (78% vs. 78%, respectively; p = 1.00). The OS rates were similar between two groups (26% vs. 39% at five years, respectively; p = 0.56). Multivariate analysis for OS revealed that complex karyotype and t(8;14) were independent prognostic factors, but not CCH acquisition. Likewise, in the 56 Ph-positive ALL patients, CCH acquisition was not significantly associated with the CR rates (92% vs. 78%, respectively; p = 0.27), and the OS rates did not significantly differ between the two groups (34% vs. 40% at five years, respectively; p = 0.90). In multivariate analysis for OS, no independent prognostic factor was identified. Conclusion: Adult ALL patients with abnormal karyotype acquired CCH at diagnosis with a frequency comparable to that of AML patients. However, unlike AML patients, CCH acquisition was more frequently observed in younger population and did not show any prognostic impact in ALL patients. These findings suggested that biological backgrounds of CCH acquisition at diagnosis were possibly different between in patients with ALL and AML. So, to confirm these important findings, clinical studies with larger study subjects are warranted. Disclosures Handa: Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-118462
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 9
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    Biological Features and Plasticity of CD56-Positive Dendritic-Like Cells: relationship to Blastic Plasmacytoid Dendritic Cell Neoplasm
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1486-1486
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1486-1486
    Abstract: Abstract 1486 Introduction: Dendritic cells (DCs) play critical roles in the induction and regulation of the innate and adaptive immune responses. Human blood DCs can be classified into plasmacytoid dendritic cell (pDC) and myeloid dendritic cell (mDC). In general, pDC is defined as lineage (Lin)-HLA-DR (DR)+CD123+CD11c-, and mDC is defined as Lin-DR+CD123+CD11c+. PDCs are a specific type of dendritic cells that is found in an immature form in the peripheral blood and that is the major interferon-alpha producing cell in response to viruses. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy that has a putative plasmacytoid dendritic cells origin. Unlike blood pDCs, the specific feature of BPDCN is the positive expression of CD56. In addition to these markers, BPDCNs can express various antigens, such as CD2, CD10, CD13, CD33 and even CD11c, that cause immunophenotypical diversity among cases. The goal of this study was to clarify the normal counterpart of BPDCN by analyzing the characteristics of CD56-positive blood Dendritic-like Cells (DLCs). Material and Methods: Human peripheral blood mononuclear cells (PBMNCs) were isolated by gradient centrifugation from healthy volunteers, and CD3, CD14, CD16 and CD19 antibodies were used as a lineage cocktail. We defined CD56+pDC-like cells (pDLCs) as Lin-DR+CD56+CD123+ cells, CD56+mDC-like Cells (mDLCs) as Lin-DR+CD56+CD123-CD11c+ cells, pDCs as Lin-DR+CD56-CD123+CD11c-cells and mDCs as Lin-DR+CD56-CD123+CD11c+cells. In some experiments, cells were purified from PBMNCs using a cell sorter. Sorted cells were analyzed for mRNA levels of toll-like receptors (TLRs), cytokines and transcriptional factors. Phagocytic activity and mixed lymphocyte reactions were analyzed by flow cytometry. Sorted cells were also analyzed after 4–6 days of culture with Fms-like tyrosine kinase 3 ligands (Flt3-L) and granulocyte macrophage colony-stimulating Factor (GM-CSF). Results: PBMCs comprised a small population of each cell type: 0.03% of CD56+pDLCs, 0.35% of CD56+mDLC, 0.93% of pDC 0.93%, and 0.60% of mDC. CD56+pDLCs had oval or U-shaped nuclei with condensed chromatin, and perinuclear halo, which is feature of pDC, was clearly observed in the cytoplasm. CD11c expression in CD56+pDLCs was lower than that in mDCs but higher than that in pDCs. CD56+pDLCs were not Natural Killer (NK) cells, as there was no expression of CD122 or other NK-specific antigens. Meanwhile, CD56+pDLCs had clear expression of BDCA2 and BDCA4, suggesting that this population was closely related to pDCs. Real-time quantitative (RQ) PCR assay revealed that TLRs were expressed in an intermediate level between pDCs and mDCs in CD56+pDLCs (CD56+pDLC vs. pDC vs. mDC: TLR2, 0.17 vs. 0.09 vs. 1.13; TLR4, 0.14 vs. 0.06 vs. 0.53; TLR7, 0.67 vs. 16.70 vs. 0.30; TLR9, 3.73 vs. 72.41 vs. 0.18). Expression of the transcription factors, E2-2, Irf8 and SpiB, in pDCs was higher than that in CD56+pDLCs, but lower than that in mDCs (CD56+pDLC vs. pDC vs. mDC: E2-2, 16.78 vs. 118.69 vs. 1.45; Irf8, 1.73 vs. 9.07 vs. 0.55; SpiB, 0.14 vs. 0.52 vs. 0.02). RQ−PCR after CpG stimulation revealed that CD56+pDLCs had lower interferon–alpha production when compared with pDCs (5.7405 vs. 360.881). Phagocytic capacity of CD56+pDLCs was lower than that of mDC or pDC (1.96% vs. 4.32 % vs. 52.6% for FITC-dextran positive cells in CD56+pDLCs vs. pDCs vs. mDCs). Allogeneic T cells proliferated less efficiently after culture with CD56+pDLCs than they did after culture with pDC. After in vitro culture with Flt3L and GM-CSF, the percentage of BDCA1-positive cells increased from 2.75% to 62.9%. Discussion: CD56+pDLCs were rare population in PBMNCs. Their phenotype and function were similar to pDCs, in part, but they expressed myeloid antigens and had lower function of phagocytosis and cytokine production than pDCs. In vitro culture suggested plasticity in the immunophenotype of CD56+pDLCs when compared with pDC and mDC. Collectively, these data suggest that CD56+pDLCs is a distinct new population of DCs that possesses a high degree of plasticity. These immunophenotypic characteristics and plasticity may influence the immunophenotypic diversity of BPDCNs. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1486.1486
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 10
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    Long Non-Coding RNA MALAT1 Is Associated with the Progression of Multiple Myeloma and Induced By Cellular Stress
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1759-1759
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1759-1759
    Abstract: Background: Recent transcriptome-wide analyses have revealed an overwhelming amount of transcribed, but not translated, non-coding RNAs capable of influencing diverse cellular processes such as proliferation, apoptosis, and motility. Long non-coding RNA (lncRNAs), which are commonly defined as transcripts 〉 200 nt in length, have emerged as a class of key regulatory RNA. LncRNAs are deregulated in diverse human cancers and associated with disease progression; however, little is known about its role in multiple myeloma (MM). To elucidate the role of lncRNAs in MM, we studied the expression patterns of several well-known lncRNAs in the plasma cells of MM, MGUS and plasmacytoma patients and the function in MM cell lines in vitro. Moreover, to reveal the distinct lncRNA signature comprehensively, we performed next-generation sequencing-based RNA sequencing. Methods: CD138+ plasma cells from bone marrow (BM) mononuclear cells were obtained from 110 MM patients, 48 MGUS patients, 19 control subjects and 1 patient with extramedullary plasmacytoma of the liver and analyzed after obtaining informed consent from all the patients. The expression levels of lncRNAs MALAT1, ANRIL, HOTAIR, HOTTIP, and XIST were determined by a RQ-PCR analysis. RNase H-activating LNA™ GapmeR antisense oligonucleotides were used to knockdown lncRNA in vitro in MM cell lines. The cell lines were then treated with bortezomib, MG132, doxorubicin and hypoxic conditions to evaluate the effects of cytotoxic stress on the lncRNA expression. This study was approved by the IRB of Gunma University Hospital in accordance with the Declaration of Helsinki. Results: A significant higher level of MALAT1 expression was observed in BM plasma cells of MM patients (4.49) compared to MGUS patients (1.51) and control subjects (0.55) (p 〈 0.001). Strikingly, MALAT1 expression in extramedullary plasmacytoma of the liver was 140-fold higher compared with BM plasma cells obtained at the same time of sampling (433.7 vs 3.21). MALAT1 expression was higher in MM patients with t(4;14) and del 17p (10.05 vs 3.90, p=0.049; 5.22 vs 2.76, p=0.03, respectively), but no difference was observed between stages according to the International Staging System (ISS) (p=0.87). Neither the overall survival nor the progression-free survival differed between patients with high and low MALAT1 expression. ANRIL expression levels were diverse according to the patients (range, 0 to 294.3), however, the median expression was significantly higher in MM patients (p 〈 0.001). HOTAIR and HOTTIP expression levels were not detected in most samples, and XIST expression was found only in female patient samples as expected. Interestingly, the MM cell lines KMS12PE, OPM2, KMS11 treated with bortezomib showed elevated MALAT1 expression by 4.3 -21.8 fold and ANRIL by 2.2-4.7 fold; however, this increase was not observed in bortezomib-resistant cell lines. Another proteasome inhibitor, MG132, and a low dose of the cytotoxic drug doxorubicin also elevated both lncRNAs in the cell lines. Hypoxic stress, which has been shown to induce MALAT1 in vascular cells, did not increase either lncRNA. MALAT1 knockdown by GapmeR did not affect cell proliferation. It has been shown that MALAT1 enhances cell motility of lung adenocarcinoma cells by influencing cell motility associated genes; however, the expression of previously reported affected genes, such as HMMR, CTHRC1 and ROD1, was not altered in the MALAT1 knockdown MM cell lines. Although t(4;14) was associated with a high MALAT1 expression in the patient samples, MMSET knockdown by siRNA did not change the MALAT1 expression in the cell lines, thus MMSET was not a regulator of MALAT1. RNA sequencing of MM and MGUS samples revealed a distinct lncRNA expression signature as well as protein coding genes. Conclusion: Significant upregulation of lncRNAs MALAT1 and ANRIL might be associated with MM progression. Given that MALAT1 is associated with lung cancer metastasis, MALAT1 might be strongly associated with extramedullary plasmacytoma formation due to its high expression in liver plasmacytoma. Genotoxic and ER stress induced by therapeutic drugs might upregulate MALAT1 expression, leading to extramedullary extension, which is a recent problem in MM treatment. Determining the distinct lncRNA signature of MM is a current important issue to clarify the molecular mechanisms underlying MM progression for the development of novel therapies. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1759.1759
    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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