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  • American Society of Hematology  (18)
  • 1
    Online Resource
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    Correlation of Clinical Features with the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Children with Juvenile Myelomonocytic Leukemia
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1528-1528
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1528-1528
    Abstract: Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by specific hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Mutations in RAS, NF1, or PTPN11 positioned in the GM-CSF signal pathway, are thought to be involved in the pathogenesis of JMML. However, no information is available on the relationship between these mutations and clinical features of JMML. The impacts of these mutations on clinical outcome also remain unclear. We tested 49 Japanese children with JMML for N-RAS, K-RAS, and PTPN11 mutations and evaluated their clinical significance. We also assessed correlations between mutational status and clinical and laboratory findings, including age at diagnosis, fetal hemoglobin (HbF), platelet count, and cytogenetic abnormality, all which have been proposed as prognostic factors for JMML. Of the 49 JMML patients, cytogenetic abnormalities were detected in 13, including 8 with monosomy 7. For 2 patients, a clinical diagnosis of neurofibromatosis type 1 (NF1) was confirmed. PTPN11 and N-/K-RAS mutations were found in 22 (45%) and 8 (16%) patients, respectively. Neither PTPN11 nor RAS mutations nor NF1 were present in 17 (35%) patients, and no simultaneous aberrations in these genes were found. In patients with the PTPN11 mutation, age at diagnosis was older (35 vs 11 months; P=0.001, or 12 months; P 〈 0.01) and HbF level was higher (31 vs 10%; P=0.03, or 16%; P 〈 0.01) than for patients with the RAS mutation or without any aberration, suggesting that the clinical outcome for patients with the PTPN11 mutation might be poorer, because a higher HbF level and older age have been reported to be poor prognostic factors. In fact, overall survival (OS) at 5 years was lower for patients with the PTPN11 mutation than for those without (20±9% vs 58±9%; P=0.02). In addition to PTPN11 mutation, age older than 24 months (P 〈 0.01) and abnormal karyotype (P=0.02) were also associated with poor prognosis for OS. Of the 49 patients, 33 received stem cell transplantation (SCT). OS probabilities for patients with and without a mutation in PTPN11 at 5 years after SCT were 25±10% and 64±12%, respectively (P=0.04). More importantly, mutation in PTPN11 was the only unfavorable factor for relapse after SCT (P 〈 0.01). Seven patients died owing to relapse and 12 from complications. All patients who died after relapse had a PTPN11 mutation. In summary, our results suggest that PTPN11-mutated JMML might be a distinct subgroup with specific clinical characteristics and a poor outcome.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1528.1528
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 2
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    Management of Adverse Events Associated with Dasatinib during Early Periods of Therapy in the Treatment of Chronic Myeloid Leukemia -a Clinical Report of Daria-01 Study
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 4537-4537
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4537-4537
    Abstract: Abstract Background: Dasatinib is a novel kinase inhibitor of BCR-ABL and SRC family kinases that has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, some patients experience treatment-related toxicity shortly after initiating dasatinib administration and are managed by drug interruption and/or dose reduction (altered treatment) which can limit the potential benefits of treatment. Methods: To determine the factors that influence compliance and the efficacy of dasatinib therapy, we conducted a phase 2 study of mid-term compliance and the effectiveness of dasatinib therapy in patients with chronic phase CML (CML-CP) (DARIA-01 Study). Treatment was administered until disease progression or intolerable toxicity, as determined by the treating physician. Dasatinib at 100 mg once daily was initially administrated. Dose interruption or reduction to 50 mg once daily was allowed after grade 2 or worse nonhematologic toxicity or grade 3 or worse hematologic toxicity. Trough plasma concentrations of dasatinib (Cmin) at steady state were assessed at 28 days of therapy. Results: In April 2014, 32 CML-CP patients were enrolled in the study, which included at least 6 months of follow-up. The median age was 53 years (range, 20–86). Twenty-four (75.0%) were previously untreated patients with CML-CP, and the remaining eight (25.0%) were switched from other tyrosine kinase inhibitors (imatinib, five patients; nilotinib, three patients) because of intolerance or resistance to these drugs. During the initial 28 days, 28 patients continued with 100 mg/day treatment, and four received doses of 50 mg/day. The incidence of altered treatment was 25% during the initial 3 months and 34% during the initial 6 months from dasatinib administration. Four patients who experienced dose reduction during the initial 3 months continued with 50 mg/day treatment thereafter at their request. Except one who experienced gastro-intestinal bleeding, all patients could continue dasatinib therapy. Age ( 〉 60 years) and Cmin divided by the given dasatinib dose (Cmin/D) were significantly correlated with a higher incidence of altered treatment during the initial 3 months (p = 0.0095) (p = 0.0083). Twenty-five (78%) patients achieved complete cytogenetic response (CCyR), and 13 (40%) achieved major molecular response at 6 months. The incidence of pleural effusion during the initial 28 days was significantly correlated with Cmin/D (p = 0.032) but was not related to the molecular response rate at 6 months (40% vs. 41%, p = 0.98). Conclusion: Current data demonstrate that patients treated with dasatinib who displayed a high Cmin/D ( 〉 1.0) value at day 28 and/or who were aged 60 and over were at a high risk for altered treatment during the early periods of therapy. Patients who experienced pleural effusion could be well managed by dose reduction and/or temporal interruption of dasatinib and could still achieve the preferable molecular response rate. Individualizing therapy by incorporating a pharmacokinetic assay would improve compliance and the efficacy of dasatinib therapy, particularly for elderly patients. Disclosures Morita: Bristol: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.4537.4537
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Interleukin-4 Promotes the Development of Tryptase and Chymase Double-Positive Human Mast Cells Accompanied by Cell Maturation
    American Society of Hematology ; 1998
    In:  Blood Vol. 91, No. 1 ( 1998-01-01), p. 187-195
    Details
    In: Blood, American Society of Hematology, Vol. 91, No. 1 ( 1998-01-01), p. 187-195
    Abstract: Human cultured mast cells (HCMCs) grown from cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin-6 (IL-6) expressed tryptase but no or low chymase in their cytoplasm. The addition of IL-4 to these cells strikingly increased chymase expression. Consequently, the activity of chymase was significantly higher in IL-4–treated mast cells than that in IL-4–nontreated mast cells, whereas the activity of tryptase and histamine content were comparable in both cells. Electron microscopic immunocytochemistry also showed that secretary granules containing chymase increased in IL-4–treated mast cells. Interestingly, the IL-4–induced increase of chymase expression in HCMCs was accompanied by morphological maturation of the cells. Cytoplasmic projections were few in IL-4–nontreated HCMCs, and a small number of secretary granules were observed, most of which were empty or partially filled with discrete scrolls with rough particles showing immaturity. In contrast, IL-4–treated HCMCs had extremely abundant cytoplasmic projections and had many secretary granules filled with electron-dense crystal materials. Taken together, immature HCMCs grown only with SCF and IL-6 expressed tryptase with no or a low amount of chymase, and addition of IL-4 promoted cell maturation together with the expression of both tryptase and a high amount of chymase. Our findings will raise a possibility of a linear pathway of human mast cell development from tryptase single positive mast cells into tryptase and chymase double positive mast cells as the cells mature and will suggest that this maturation process is promoted by IL-4.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V91.1.187.187_187_195
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1998
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    IKZF1 Deletion Is Strongly Associated with Risk of Relapse in Intermediate Risk Group in JACLS ALL02 Cohort
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1455-1455
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1455-1455
    Abstract: Abstract 1455 Introduction: Despite the progress of the current therapy, approximately 20 % of pediatric patients with B-cell-presursor (BCP)-ALL experience relapse who had no conventional adverse prognostic factor. Recently, alteration of the IKZF1 gene has been reported to be associated with a poor outcome in pediatric BCP-ALL without BCR-ABL. In addition, it is also reported that a significant proportion of these cases with the alteration of IKZF1 shared the point mutation of JAK2 and over-expression of cytokine receptor-like factor 2 (CRLF2). Herein, in order to assess the prognostic value of these genetic abnormalities in Japanese cohort, we conducted genetic analysis of IKZF1, JAK2 and CRLF2 in pediatric BCP-ALL. Materials and Methods: Diagnostic bone marrow or peripheral blood samples of 215 pediatric BCP-ALL patients treated according to Japan Association of Childhood Leukemia Study (JACLS) ALL02 protocol from April, 2002 to May, 2008 were examined in this study. All patients were categorized into high risk (HR) group defined as follows;(1) initial white blood cell counts more than 10,000 /μl, (2) age at diagnosis is 〉 10 years and (3) good response to initial predonisolone (PSL) treatment ( blast counts in peripheral blood is less than 1,000 /μl after one week PSL treatment). Ph+ALL and infantile ALL patients were excluded in this protocol. The patients with Down syndrome were also excluded in this genetic analysis. The deletion of IKZF1 was determined using multiplex ligation-dependent probe amplification (MLPA) in 212 patients whose diagnostic DNA samples were available. The expression of isoform of IKZF1 was determined by RT-PCR in 113 patients whose diagnostic RNA samples were available. The expression level of CRLF2 was also determined by real time RT-PCR in 112 patients and over-expression was defined as over ten times more than median expression value. The presence of P2RY8-CRLF2 fusion was examined by RT-PCR or MLPA in the patients with CRLF2 over-expression or IKZF1 deletion. JAK2 mutations were also determined by direct sequencing of the exon 16, 20 and 21 in the patients with IKZF1 deletion. Results: The deletion of IKZF1 gene was present in 19 of 212 (9.0 %) patients. In detail, the mono-allelic deletion of entire IKZF1 gene was present in 10 of 19 patients. On the other hand, the expression of dominant-negative IK6 isoform was present in 9 of 112 (8.0%) patients including 12 patients with IKZF1 deletion. The expression of IK6 was present in 4 of 12 (33.3%) IKZF1 deleted patients. Interestingly, 5 of 9 patients with IK6 expression had no alteration of IKZF1 gene. In terms of CRLF2, over-expression was detected in 16 of 112 patients (14.3 %). However, P2RY8-CRLF2 fusion was not detected in these 16 patients with altered CRLF2 expression. Strikingly, none of the patients with IKZF1 deletion (n=19) had either P2RY8-CRLF2 fusion or JAK2 exon 16, 20 and 21 mutation. Patients with IKZF1 gene deletion had significantly worse relapse rate than those without IKZF1 deletion (7/19 vs 22/193, p 〈 0.01). On the contrary, none of the patients with IK6 expression experienced relapse. Discussions: This study confirmed that the presence of IKZF1 deletion was strongly correlated with risk of relapse in intermediate risk group in JACLS ALL02 cohort. Thus, we expect that IKZF1 deletion is an independent predictor of treatment outcome and represents a candidate of prognostic marker to be integrated in future algorithms for early risk stratification in pediatric BCP-ALL. Strikingly, point mutation of JAK2 exon 16, 20 and 21 or P2RY8 -CRLF2 fusion was rarely present even in BCP-ALL patients with IKZF1 deletion. There might be unrevealed class I mutation cooperating with IKZF1 alteration in Japanese BCP-ALL cohort. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1455.1455
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 5
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    The Value of Combination of Serum L-Kynurenine Level and Expression of Indoleamine 2,3-Dioxygenase mRNA As a Prognostic Factor in Acute Myeloid Leukemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 4947-4947
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4947-4947
    Abstract: Introduction: The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the metabolism of the essential amino acid tryptophan along the L-kynurenine (KYN) pathway. Some metabolites derived from tryptophan via IDO catalysis such as KYN block antigen-driven specific T-cell proliferation and induce T-cell death. IDO activity might play an important role in regulating the immune response exerted by antigen presenting cells. Indeed, we have recently reported the utility of either serum KYN or the expression of IDO mRNA as prognostic factors for acute myeloid leukemia (AML) [Leuk Lymphoma: In press, Leuk Lymphoma 56:1398-405]. Here, we investigated the value of combination of serum KYN level and expression of IDO mRNA as a prognostic factor in AML patients. Patients and Methods: AML was diagnosed according to the WHO 2008 criteria based on standard cytological and histochemical assessments of smears of cryopreserved bone marrow cells from 29 consecutive adult patients between December 2005 and March 2014. All patients in this study had been enrolled in both our serum KYN study and expression of IDO mRNA study. All follow-up data were fixed on August 1, 2014. KYN concentrations in serum samples were measured by high-performance liquid chromatography. Bone marrow-derived mononuclear fractions were separated and IDO expression was analyzed by using extracted mRNA amplified by PCR. Results: We examined expression of IDO mRNA and serum L-kynurenine in a total of 29 patients (median age, 55 years; range, 18-74 years). Among them, 11, 14 and 4 patients were classified as having favorable, intermediate and unfavorable cytogenetic risk, respectively. Twenty seven patients underwent standard intensive chemotherapy, mainly consisting of cytosine arabinoside (Ara-C) and anthracycline. All patients with acute promyelocytic leukemia (n = 5) received induction therapy containing all-trans retinoic acid. Two patients received less intensive chemotherapy [J Cancer Res Clin Oncol. 133:547-53.], because of poor performance status. The median serum KYN level was 1.63 µM (range, 0.66-5.27 µM). We set the L-kynurenine cut-off value at 2.4 µM according to our previous report. The RT-PCR results showed that bone marrow from 12 (41%) patients were IDO-positive. No significant correlation was identified between serum KYN level and IDO expression. Complete remission (CR) rates were 57% and 86% for patients with KYN levels ≥2.4 and 〈 2.4 µM, respectively. CR with initial therapy was obtained by 67% of patients with positive IDO expression, compared to 88% with negative IDO expression, respectively. Three-year OS rates were 0% and 76% for patients with KYN ≥2.4 and 〈 2.4 µM, respectively (P 〈 0.0001), and 37% and 77% for patients with IDO-positive and IDO-negative AML, respectively (P=0.0511) (Figs. 1A, B). Three-year OS rates were 83%, 50% and 0% for patients with low KYN and IDO-negative, either high KYN or IDO-positive, and high KYN and IDO-positive, respectively (P 〈 0.005; Fig. 1C.). Discussion: In the present study, we assessed the significance of serum concentration of KYN, IDO mRNA expression, and the combination of these two factors in AML patients and demonstrated their prognostic value. High serum KYN concentration was associated with poor outcomes of AML. While, expression of IDO mRNA had a tendency with poor prognosis, it did not show significant difference on the survival of AML patients. These results were due to the small sample size in this study, and will have to be confirmed in future studies with larger numbers of patients.When we compare these two factors as prognostic value, serum concentration of KYN may be more useful because measurement of serum concentration of KYN is easier than IDO mRNA expression and identifies ultra-high risk patients. In contrast, serum concentration of KYN has poor separation capacity for many other patient, which can be further subdivided by adding measurement of IDO mRNA expression. Indeed, the combination of serum concentration of KYN and IDO mRNA expression was associated with poor outcomes of AML and was able to subdivide the AML patients to three different prognostic groups clearly. Conclusion: This study clearly showed the prognostic value of the combination of serum KYN concentration and IDOm RNA expression for AML patients. Figure 1. Overall survival according to serum L-kynurenine concentration and IDO expression. Figure 1. Overall survival according to serum L-kynurenine concentration and IDO expression. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.4947.4947
    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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  • 6
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    Hepatocyte Growth Factor Is Constitutively Produced by Human Bone Marrow Stromal Cells and Indirectly Promotes Hematopoiesis
    American Society of Hematology ; 1997
    In:  Blood Vol. 89, No. 5 ( 1997-03-01), p. 1560-1565
    Details
    In: Blood, American Society of Hematology, Vol. 89, No. 5 ( 1997-03-01), p. 1560-1565
    Abstract: Bone marrow (BM) stromal cells are required for normal hematopoiesis. A number of soluble factors secreted by these cells that mediate hematopoiesis have been characterized. However, the mechanism of hematopoiesis cannot be explained solely by these known factors, and the existence of other, still unknown stromal factors has been postulated. We showed that hepatocyte growth factor (HGF ) is one such cytokine produced by human BM stromal cells. BM stromal cells were shown to constitutively produce HGF and also to express the c-MET/HGF receptor. The production of HGF was enhanced by addition of heparin and phorbol ester. Dexamethasone and tumor growth factor-β (TGF-β) inhibited the production of HGF. Interleukin-1α (IL-1α) tumor necrosis factor-α (TNF-α), and N6,2′-o-dibutyryl-adenosine-3′:5′-cyclic monophosphate (dbc-AMP) showed no obvious influence on HGF production. Western blot analysis of HGF derived from BM stromal cells showed two bands at 85 and 28 kD corresponding to native and variant HGF, respectively. Addition of recombinant HGF significantly promoted the formation of burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte erythroid macrophage (CFU-GEM) by BM mononuclear cells in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF ), but the formation of CFU-GM was not modified. However, HGF had no effects on colony formation by purified CD34+ cells. Within BM mononuclear cells, c-MET was expressed on a proportion of cells (CD34−, CD33+, CD13+, CD14+, and CD15+), but was not found on CD34+ cells. We conclude that HGF is constitutively produced by BM stromal cells and that it enhances hematopoiesis. In addition, expression of c-MET on the stromal cells suggests the presence of an autocrine mechanism, operating through HGF, among stromal cells.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V89.5.1560
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1997
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  • 7
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    A Randomized Phase II/III Study of R-THP-Cop Vs R-CHOP for Patients Younger Than 70 Years with DLBCL
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3078-3078
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3078-3078
    Abstract: Introduction: Since the introduction of rituximab (R), a prognosis of diffuse large B cell lymphoma (DLBCL) is markedly improved. The rituximab-CHOP (R-CHOP) regimen, consisting of R, cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisolone (PSL), has become the current standard treatment for patients with DLBCL. On the other hand, the cardiotoxic problem due to DXR still remains. Pirarubicin (tetrahydropyranyl adriamycin: THP), a derivative of DXR, was reportedly an anthracyclin with less cardiotoxicity than DXR. Before introduction of rituximab, we reported the equivalent result between CHOP and THP-COP using THP instead of DXR regimen in aggressive non-Hodgkin’s lymphomas (74% of enrolled patients were DLBCL) (Tsurumi H et al. J Cancer Res Clin Oncol. 2004). In addition, we reported the efficacy and safety of R-THP-COP regimen for DLBCL in phase II study (Hara T et al. J Cancer Res Clin Oncol. 2010). Here, we prospectively compared the efficacy and safety of R-THP-COP and R-CHOP regimens as a clinical trial in Gifu Hematology Study Group. Methods: In a prospective randomized phase II/III study, we assigned 80 patients (40 for R-CHOP or 40 for R-THP-COP) less than 70 years of age with previously untreated DLBCL, from July 2006 through September 2013. A diagnosis of DLBCL was histologically confirmed by 2 or 3 experts of pathology, according to the World Health Organization classification 2008. Patients who were infected with HIV or HTLV-1 were excluded. All patients provided written informed consent in accordance with the institutional guideline of Gifu University Graduate School of Medicine and the Declaration of Helsinki. The regimens consisted of R 375mg/m2 (day 1), DXR or THP 50 mg/m2 (day3), CPA 750 mg/m2 (day 3), VCR 1.4 mg/m2 (day 3) and PSL 100 mg/body for 5 days every 2 weeks for 6-8 cycles. The primary end point was the complete response rate, with the duration of overall survival (OS), safely and progression-free survival (PFS) as secondary end points. Results: No significant differences (N.S.) in known prognostic factors (elderly patients, advanced clinical stage, poor performance status, elevated LDH and number of extranodal sites 〉 1) were found between the both groups. At a median follow-up of 57 months (7 - 91 months), CR rate was 88.6% (87.2% for R-CHOP, 90.0% for R-THP-COP; P-value N.S.). The 2-year OS rates were 89.6% (87.1% for R-CHOP, and 92.1% for R-THP-COP; N.S.), respectively and 2-year PFS rates were 83.0% (79.0 % for R-CHOP, and 87.0 % for R-THP-COP; N.S.), respectively. In analyses of safety aspects, no cardiotoxicity of grade 3 or higher occurred in both groups. No serious adverse events were observed except for therapy-related acute myeloid leukemia in a patient with R-THP-COP group. The highest frequent adverse event was febrile neutropenia (32.5% in R-CHOP, 40% in R-THP-COP; N.S.). Therapy-related death was not observed. Conclusions: R-THP-COP regimen produced results equivalent to those of R-CHOP regarding efficacy and safety in DLBCL patients less than 70 years of age. This regimen might be an alternative therapy instead of R-CHOP for patients with DLBCL. Further large clinical study should be considered to confirm efficacy and safety of R-THP-COP compared with R-CHOP. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3078.3078
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Benefit of Consolidative Radiotherapy in Patients with Limited Stage Diffuse Large B-Cell Lymphoma in the Rituximab Era
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 4210-4210
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4210-4210
    Abstract: Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma and the most common lymphoid neoplasm in adults. In the pre rituximab era, the standard therapy for patients with limited stage DLBCL had been three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) followed by involved-field radiotherapy (IFRT). The addition of rituximab has revolutionized the treatment of DLBCL. Rituximab combined with CHOP (R-CHOP) has been established as the standard treatment for patients with DLBCL. However, the role of consolidative radiotherapy (RT) in the treatment of limited stage DLBCL in the rituximab era is controversial. Patients and Methods: We retrospectively analyzed 108 patients with limited stage DLBCL who received R-CHOP or R-THP-COP (rituximab plus, cyclophosphamide, pirarubicin, vincristine and prednisone) regimen between June 2004 and August 2015. We compared overall survival (OS) and progression-free survival (PFS) according to the treatment. OS was calculated from the date of initiation of chemotherapy to the date of the last follow-up or death. PFS was calculated from the date of initiation of chemotherapy to the date of progression disease, death, or last contact, whichever occurred first. Survival was estimated from Kaplan-Meier curves and compared using the log-rank test. P 〈 0.05 was considered statistically significant. Weighted Cox proportional hazards regression modeling with the inverse probability weighted (IPW) estimators method adjusting to propensity for RT was used to account for differences in baseline characteristics. Results: Median age at diagnosis was 66 years (19-88 years), with 61 males and 47 females. Forty-three patients (40%) had stage I, and 65 patients (60%) received consolidative RT after chemotherapy. Patients who received consolidative RT were significantly younger (65 vs 72, P 〈 0.01) and were more likely to have stage I disease (51% vs 23%, P 〈 0.01). The median number of chemotherapy cycles was 4 (range 3-8) in patients who received RT, and 6 (range 3-8) in patients who did not. Median follow-up was 4.3 years (0.3-10.9 years), and the 5-year OS (92% vs 63%, P 〈 0.01) and PFS (87% vs 65%, P 〈 0.01) were significantly higher for patients who received RT than those who did not. Using IPW adjustment, RT remained predictive of OS (HR 0.30, CI 0.13-0.72, P 〈 0.01) and PFS (HR 0.47, CI 0.22-0.99, P 〈 0.05). Conclusion: Our results suggest that consolidative RT improves OS and PFS in patients with limited stage DLBCL in the rituximab era. Although consolidative RT seems to be gradually phased out by chemotherapy alone, it is still an important treatment strategy. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.4210.4210
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
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  • 9
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    The Pretreatment Controlling Nutritional Status (CONUT) Score Is an Independent Prognostic Factor in Elderly Patients with Diffuse Large B-Cell Lymphoma
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4210-4210
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4210-4210
    Abstract: [Backgrounds] The controlling nutritional status (CONUT), one of the useful parameter of nutritional assessment tools, is a significant prognostic factor for various solid tumors. The CONUT score is an index calculated from the following factors; the serum albumin concentration (Alb), the total peripheral lymphocyte counts (Lymph) and total cholesterol concentration (Chol) (Table 1). Some predictive models specified the relationship between nutritional status and the prognostic value of malignant disease have been proposed. However, the role of the CONUT score in predicting clinical outcomes of diffuse large B cell lymphoma (DLBCL) patients has not been investigated. The aim of this study is to elucidate the impact of the pretreatment CONUT score on survival in patients with DLBCL who received rituximab (R) plus chemotherapy. [Patients and Methods] We retrospectively investigated 240 patients who were histologically diagnosed with DLBCL between June 2004 and November 2015. All patients received R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or R-THP-COP (cyclophosphamide, tetrahydropyranyl-adriamycin, vincristine, prednisone) regimen. We defined the best cutoff value of the CONUT score as 3 using a receiver operating characteristic curve. [Result] The mean and median of the CONUT score of all patients (median age 68, range 19 - 93, 140 male and 100 female) were 2.85 and 2 (range 0 - 12). The data of each parameter's median and range constituting CONUT (Alb, Lymph, Chol) was as follows: 4 (1.9 - 5.3), 1170 (105 - 13192), and 173 (49 - 287), respectively. Patients with High-CONUT score (≥3, n = 109) had significantly lower overall survival (OS) and progression-free survival (PFS) than those with Low-CONUT score (≤2, n = 131) (5-year OS, 63.0 vs. 83.6%, P = 0.006; 5-year PFS, 56.5 vs. 78.0%, P = 0.003). The conventional predictive factors such as International Prognostic Index (IPI; age, performance status, Ann Arbor stage, extra-nodal involvement sites and lactate dehydrogenase) were all significantly associated with a worse OS and PFS. A subsequent subgroup analysis based on age indicated that 70 years or elder patients (n = 108) with High-CONUT had a significantly worse 5-year OS and PFS as compared to Low-CONUT patients (OS, 50.0 vs. 77.2%, P = 0.008; PFS, 41.6 vs. 77.6%, P = 0.0004). In contrast, no significant differences were observed in the OS and PFS when High- and Low-CONUT patients less than 70-year-old were compared. The multivariate analysis of all of the significant parameters in patients older than 70 years indicated that High-CONUT was an independent prognostic factor for PFS (HR = 2.20, 95 % CI = 1.08-4.66, p = 0.03). [Discussion] The serum Alb concentration is a reliable indicator of nutritional status and systemic inflammation. Total peripheral Lymph, which play an important role in the immune response to the tumor, are known to indicate the immunological and nutritional status. It is also reported that Chol, an indicator of a patient's caloric reserves, increased the antigen-presenting function of monocytes. Organ function decreases with aging, and many elderly patients have comorbidities that compromise their capacity to tolerate standard dose chemotherapy. In addition, intensive chemotherapy is often complicated by deterioration of nutritional status as the elderly. Hence, elderly patients are an extremely heterogeneous population and optimal treatment strategy should be adapted in consid eration of comorbidities. On the other hand, DLBCL is a curable disease even in the elderly population. Therefor prognostic stratification in older population should be focused on the real biological age of patients and on primary variables that reflect tumor aggressiveness, immune interaction and nutritional status. In this respect, the pretreatment CONUT score is considered suitable for prognostic model of elderly patients. Previously, we have reported that sarcopenia is an independent poor prognostic factor for PFS in male patients with DLBCL (Ann Hematol, 2015). In this cohort, sarcopenia has no effect on PFS in elderly patients. [Conclusion] The pretreatment CONUT score is easily able to predict the prognosis of elderly patients with DLBCL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-110055
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Interleukin-4 Promotes the Development of Tryptase and Chymase Double-Positive Human Mast Cells Accompanied by Cell Maturation
    American Society of Hematology ; 1998
    In:  Blood Vol. 91, No. 1 ( 1998-01-01), p. 187-195
    Details
    In: Blood, American Society of Hematology, Vol. 91, No. 1 ( 1998-01-01), p. 187-195
    Abstract: Human cultured mast cells (HCMCs) grown from cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin-6 (IL-6) expressed tryptase but no or low chymase in their cytoplasm. The addition of IL-4 to these cells strikingly increased chymase expression. Consequently, the activity of chymase was significantly higher in IL-4–treated mast cells than that in IL-4–nontreated mast cells, whereas the activity of tryptase and histamine content were comparable in both cells. Electron microscopic immunocytochemistry also showed that secretary granules containing chymase increased in IL-4–treated mast cells. Interestingly, the IL-4–induced increase of chymase expression in HCMCs was accompanied by morphological maturation of the cells. Cytoplasmic projections were few in IL-4–nontreated HCMCs, and a small number of secretary granules were observed, most of which were empty or partially filled with discrete scrolls with rough particles showing immaturity. In contrast, IL-4–treated HCMCs had extremely abundant cytoplasmic projections and had many secretary granules filled with electron-dense crystal materials. Taken together, immature HCMCs grown only with SCF and IL-6 expressed tryptase with no or a low amount of chymase, and addition of IL-4 promoted cell maturation together with the expression of both tryptase and a high amount of chymase. Our findings will raise a possibility of a linear pathway of human mast cell development from tryptase single positive mast cells into tryptase and chymase double positive mast cells as the cells mature and will suggest that this maturation process is promoted by IL-4.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V91.1.187
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1998
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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