Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4447-4447

Abstract: Background: Isocitrate dehydrogenase (IDH)-1 and -2 are TCA cycle-involved enzymes which convert isocitrate to alpha-ketoglutarate. Mutations that alter the enzymatic activity causes accumulation of a mal-metabolite D-2-hydroxyglutarate, which results in inhibition of DNA methylation and tumorigenesis. IDH-1 and IDH-2 mutation are present in approximately 7-10% and 10% of patients with acute myeloid leukemia (AML), respectively. Recently, whole exome sequencing has been used for the next-generation sequencing of AML, and certain gene mutations have been identified in patients with AML. The treatment strategies for leukemia have undergone drastic changes with the rapid development of new drugs. However, the proper use of newly developed agents poses a major challenge in AML treatment. Genome profiling analysis can be used to select the optimal treatment for patients with newly diagnosed AML. IDH mutant-specific inhibitors such as ivosidenib and enasidenib were already approved in the US, and combination treatment with venetoclax and Azacitidine was recently approved in Japan. Methods and Results: We lunched an actionable mutation profiling multicenter study named Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel. The primary outcome was the frequency of each genomic alteration, as determined using F1H, which is a comprehensive genome profiling test based on next-generation sequencing, in the AML specimens. The secondary outcome was the association between each genomic alteration and the clinicopathological characteristics, prognosis, and quality of specimens used in the genetic analysis. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) fulfillment of either of the following conditions: i) newly diagnosed AML unfit for standard treatment (ND-unfit AML) or ii) R/R-AML; 3) sufficient sample collection via bone marrow aspiration; 4) Age of participants 20 years or above during registration; 5) provision of written informed consent by participants. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. The median turnaround time was 13 days (minimum 8 days). We found 13 patients (7.3%) with IDH1 mutation and 17 patients (9.6%) with IDH2 mutation out of 177 patients who joined this study and the F1H report was successfully returned. Only one patient had both mutations, and each mutation was mutually exclusive in all the other patients (Figure 1). The major amino acid alteration of IDH1 and IDH2 were R132C/G/H/L and R140Q/W, respectively. Frequently co-occurring mutations include FLT3 (44.8%), NPM1 (34.5%), DNMT3A (31.0%) and RUNX1 mutation (20.7%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS and PTPN11) were seen in 6 patients (20.7%). Any gene alterations didn't show statistically significant co-occurrence with IDH1 and IDH2 mutation. Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating FLT3-mutated AML. Also in this cohort, we are examining the properties and distribution of IDH1/2 mutations during treatment with FLT3 inhibitors. In the several patients, expansion and persistence of IDH mutated clones seemed to be cause of resistance (Figure 2 as the representative result). The detailed clinical outcomes of AML patients with IDH1/2 mutations are under investigation. Conclusions: In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified IDH-1/2 mutation that can be used as therapeutic targets in AML, which have rarely been identified thus far. Figure 1 Figure 1. Disclosures Shibayama: Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Fujimoto: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Mundi Pharma: Honoraria; Essentia Pharma Japan: Research Funding. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria. Kuroda: Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Nippon Boehringer Ingelheim: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Asahi kasei: Research Funding; Eli Lilly: Research Funding; MSD: Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Kyowa Kirin: Other: Personal fees, Research Funding; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Huya Japan: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding. Ono: Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Eizai: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Genmab: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Chugai: Honoraria, Research Funding; Symbio: Honoraria; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Minami: Novartis Pharma KK: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; CMIC: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-149801

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2639-2639

Abstract: Abstract 2639 INTRODUCTION: Recent studies have suggested that one mechanism of immune escape could be catabolism of the essential amino acid tryptophan, via indoleamine 2,3-dioxygenase (IDO) along the kynurenine pathway. Some metabolites derived from tryptophan by IDO, such as L-kynurenine, block antigen-driven specific T-cell proliferation and induce T-cell death. IDO activity thus plays an important role in regulating immune responses exerted by antigen-presenting cells (APCs) and also provides transformed cells with a potent tool to help escape from assault by the immune system. We have recently been able to clarify the utility of either serum L-kynurenine or tissue IDO expression as prognostic factors for DLBCL patients treated using R-CHOP. The present study therefore examined the serum level of L-kynurenine and tissue IDO expression simultaneously in DLBCL patients in an attempt to identify patients showing truly poor prognosis. MATERIALS AND METHODS: The study protocol used a retrospective case series design that was approved by our institutional review board. We investigated DLBCL patients who had been histologically diagnosed according to the WHO classification of hematopoietic tumors between December 2003 and November 2006. All serum samples were obtained on admission before starting any treatments. Informed consent was obtained from all patients for the use of samples in this study. Tumor tissue was obtained from every patient by lymph node biopsy before initiation of therapy. Patients were assigned to receive six to eight cycles of R-CHOP or R-THP-COP therapy. Each regimen consisted of rituximab (375 mg/m2 on day 1), cyclophosphamide (750 mg/m2 on day 3), doxorubicin (DOX) or tetrahydropyranyl-adriamycin (THP) (50 mg/m2, given as a 30-min infusion on day 3), vincristine (1.4 mg/m2 on day 3, with a maximal dose of 2.0 mg), and prednisolone (100 mg/day on days 3–7). We measured serum concentrations of L-kynurenine by high-performance liquid chromatography (HPLC), and serum levels of sTNF-Rs (p55, TNF-R1; p75, TNF-R2) by ELISA. And we examined IDO expression in DLBCL tissues by immunohistochemical staining in a total of 119 patients. RESULTS: Median serum levels of L-kynurenine were significantly higher in DLBCL patients (1.598 mM; range, 0.489–5.066 mM) than in healthy volunteers (1.133 mM; range, 0.752–1.388 mM). And we found that lymphoma cells expressed IDO in 32% cases. We therefore classified cases as IDO-positive DLBCL or IDO-negative DLBCL based on whether lymphoma cells themselves expressed IDO. No significant correlation was identified between serum L-kynurenine level and IDO expression. Serum L-kynurenine level showed a significant positive correlation with concentrations of sTNF-R1 and sTNF-R2 in IDO-negative DLBCL patients. CR rates with IDO-positive and IDO-negative DLBCL were 42% and 75%, respectively (p=0.012). Three-year OS rates were 55% and 78% for patients with L-kynurenine ≥1.5 and 〈 1.5 mM, respectively (p=0.027), and 44% and 75% for patients with IDO-positive and IDO-negative DLBCL, respectively (p=0.0017). Univariate Cox analysis identified the following prognostic factors: IDO expression, serum kynurenine, PS, and multiple site extranodal involvement. Multivariate analysis of these four parameters showed that positive IDO expression and serum kynurenine ≥1.5 mM were significant prognostic factors. We analyzed patients' outcome according to serum concentration of L-kynurenine and IDO expression of lymphoma cells at diagnosis. Patients with low kynurenine and IDO-negative showed the best outcomes, while patients with high kynurenine and IDO-positive showed the poorest outcome. This combination distinguishes 3 separate prognostic groups of “very good”, “good”, and “poor”, with 3-year OS ranging from 84.1% to 31.1% (p 〈 0.001, Figure). CONCLUSION: IDO activity might play an important role in the disease activity of DLBCL. The combination of tissue IDO expression and serum level of L-kynurenine is a useful tool to predict the prognosis of 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.V118.21.2639.2639

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1555-1555

Abstract: Abstract 1555 Background: Tumor-infiltrating immune cells perform important functions in host immune reaction against tumor cells including diffuse large B cell lymphoma (DLBCL). Recently, variable tumor-infiltrating cells were reported to give a influence for prognosis, for example, regulatory T cell (T reg), cytotoxic T cell, macrophage and mast cell etc. Among these microenvironmental cells, we focused on Treg cell, and we assessed the distribution and prognostic significance of these cells in DLBCL. The forkhead/winged helix transcription factor 3 (FOXP3) is a transcriptional factorshown to be the key control gene in the development and function of Tregs both in mice and humans. Patients and Methods: We examined samples from 94 patients (54 men and 40 women; median age, 70 years) at diagnosis who were prospectively enrolled between 2002 and 2008. All patients treated with R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). The pattern of FOXP3 protein expression was evaluated using immunehistochemistry in paraffin-embeded tissue samples. In addition, these samples were stained with antibodies for CD10, bcl-6 and MUM-1 via tissue microarray to classify into subgroups. Results: The median percentage of FOXP3+ cells was 91/mm2 (range 4–2100 /mm2). Patients with poor performance status (PS), and high serum lactate dehydrogenase (LDH) showed lower numbers of FOXP3+ cells. (PS; p= 0.014, LDH; p=0.0048) Patients with high counts of FOXP3+ cells ( 〉 90/mm2) have better prognosis than those of low counts (5 year (5-y) overall survival (OS); 72.1%, 49.7% p=0.024, respectively). Although no prognostic difference was observed between GCB type and non-GCB type (5-y OS: GCB 71.2%, non GCB 53.1%, p=0.12), low counts of FOXP3+ cell and non-GCB type patient was poorer prognosis than high counts and non GCB type. (low 5-y OS 31.2%, high 5-y OS 69.8% p=0.02). Conclusion: Increased count of FOXP3+ tumor-infiltrating cell might predict better prognosis of 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.V120.21.1555.1555

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Internal Medicine, Japanese Society of Internal Medicine, Vol. 57, No. 21 ( 2018-11-1), p. 3175-3177

Type of Medium: Online Resource

ISSN: 0918-2918 , 1349-7235

URL: Article

DOI: 10.2169/internalmedicine.0869-18

Language: English

Publisher: Japanese Society of Internal Medicine

Publication Date: 2018

detail.hit.zdb_id: 2202453-0

In: Ophthalmology, Elsevier BV, Vol. 126, No. 10 ( 2019-10), p. 1385-1398

Type of Medium: Online Resource

ISSN: 0161-6420

URL: Article

DOI: 10.1016/j.ophtha.2019.04.042

Language: English

Publisher: Elsevier BV

Publication Date: 2019

In: Immunogenetics, Springer Science and Business Media LLC, Vol. 29, No. 4 ( 1989), p. 235-240

Type of Medium: Online Resource

ISSN: 0093-7711 , 1432-1211

URL: Article

DOI: 10.1007/BF00717907

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 1989

detail.hit.zdb_id: 1398344-1

SSG: 12

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3059-3059

Abstract: BACKGROUND: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is relatively rare, accounting for only 10% to 15% of non–Hodgkin's lymphomas, and is characterized by disseminated disease, with systemic symptoms, bone marrow involvement, and extranodal disease. There is no general consensus regarding the preferred induction chemotherapy for PTCL-NOS. CHOP regimen consisting of cyclophosphamide (CPA), doxorubicin (DOX), vincristine (VCR) and prednisone (PSL) has been the most frequently employed regimen for PTCL-NOS, but the overall survival in each IPI category appears lower in patients with most PTCL-NOS than seen in diffuse large B-cell lymphoma. Pirarubicin (tetrahydropyranyladriamycin: THP), a derivative of DOX, is reportedly an anthracyclin with less cardiotoxicity than DOX, because the cardiac sympathetic dysfunction and cardiac mitochondrial damage were less common with THP than those with doxorubicin. We previously reported THP-COP regimen consisting of THP, CPA, VCR, and PSL produced resulted equivalent to CHOP regimen regarding efficacy and safety in patients with aggressive non-Hodgkin's lymphoma (Tsurumi H et al. JCRCO 2004). In addition The Japanese Clinical Study Group of THP Lymphomas in the Elderly reported that T-cell lymphomas had a significantly better response to THP-COP than CHOP, and no such difference was observed in B-cell lymphoma. Therefore, we conducted a retrospective analysis to confirm the efficacy of THP-COP in the treatment of PTCL-NOS. PATIENTS AND METHODS: The study protocol employed a retrospective, consecutive entry design. We retrospectively analyzed 61 patients with PTCL-NOS who had received THP-COP or CHOP in 5 institutes of Gifu Hematology Study Group between December 1995 and March 2013. A diagnosis of PTCL-NOS was confirmed histrogically according to the World Health Organization classification. We exclude patients who had previously treated with any chemotherapy for lymphoma, and were diagnosed as Adult T-cell leukemia/lymphoma or angioimmunoblastic T-cell lymphoma. CHOP regimen composed CPA (750 mg/m2), DOX (50 mg/m2), VCR (1.4 mg/m2, maximal dose 2.0 mg) and PSL (100mg/body, administered for 5 days). In THP-COP regimen, THP (50 mg/m2) was used instead of DOX. These regimens were performed every 14 to 21 days. Thirty patients received THP-COP, 31 received CHOP. There were no significant differences in known prognostic factors include the international prognostic index (IPI) and prognostic index for T-cell lymphoma (PIT) between two groups. The median cycles of treatment were 6 in both groups. The median follow-up times were 25 and 19 months, respectively. RESULT: Complete remission (CR) rates in the patients with THP-COP and CHOP were 53% and 55% (P=0.906), 3-yr overall survival (OS) rate 68% and 51% (P=0.096), and 3-yr progression free survival (PFS) rate 46% and 27% (P=0.078), respectively. Although there were no significant differences between two groups, THP-COP regimen had a tendency of better prognosis. In patients with low IPI (Low or Low-intermediate), THP-COP had significantly better 3yr-OS (100% vs 63%, P=0.002) and 3yr-PFS (69% vs 34%, P=0.002). Same difference was observed in patients with low PIT (group1 or 2), but was not observed in patients with high IPI (High-intermediate or High) or PIT (Group3 or 4). Fatal non-hematological adverse event did not occur in both groups. CONCLUSION: Our study showed THP-COP produced resulted equivalent to CHOP regarding efficacy and safety in patients with PTCL-NOS. Moreover, THP-COP had a tendency of better prognosis compared with CHOP. In patients with low IPI or PIT, THP-COP had significantly better prognosis. This result indicates that THP-COP is an effective and well tolerated regimen for patients with PTCL-NOS, and might be translated into improving survival in comparison with CHOP. Further large study is needed to clarify the difference between the two regimens. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3059.3059

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1515-1515

Abstract: BACKGROUND: Bowel perforation after chemotherapy is a serious life-threatening complication of diffuse large B cell lymphoma (DLBCL) involving gastrointestinal tract. R Vaidya et al reported that 9 % of patients with gastrointestinal lymphoma developed a perforation, of which 55% occurred after chemotherapy, and DLBCL was the most common lymphoma associated with perforation (R Vaidya et al Ann Oncol 2013). We assume that the dose reduction of chemotherapy may have advantages to reduce the risk of gastrointestinal perforation and shorten the duration of neutropenia. This study aimed to investigate the incidence of gastrointestinal perforation after chemotherapy, whether reduced dose intensity chemotherapy could reduce the risk of the bowel perforation and how therapeutic modalities influence on the prognosis. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 348 consecutive patients who were diagnosed as having DLBCL at the Gifu University Hospital between August 2004 and April 2015. Eighty-six patients (86/348, 24.7%) were identified to have gastrointestinal involvement of DLBCL by biopsy. The prognosis of DLBCL patients with GI involvement was retrospectively investigated regarding treatments. RESULTS: The involved sites were gastric (51 patients, 48.1%), duodenal (7 patients, 6.6%), colorectal (6 patients, 5.7%), small intestine (36 patients, 34.0%) with duplicate counts permitted. Fourteen patients (14/86, 16.3%) were provided surgical treatment prior to chemotherapy since many of them had already suffered from serious complications such as ileus, perforation and bleeding. Sixty-five patients (65/86, 75.5%) received R-CHOP or CHOP like regimen ± radiation therapy as a first-line chemotherapy. As for remaining patients, two patients received R-hyperCVAD regimen because their histology were Burkitt like, and another patients received Rituximab ± other low dose chemotherapy for their frailness. The 45 patients (45/65, 69.2%) of them received reduced dose intensity (RDI) chemotherapy at the first course because increased risk of gastrointestinal perforation with chemotherapy was concerned about by endoscopic findings. The reduction rates of chemotherapy determined by the attending physician were approximately from 10% to 50%. Six patients (6/65, 9.23%) developed gastrointestinal perforation after chemotherapy (stomach 1, duodenum 0, small intestine 5, colon 0). Three of them received full dose chemotherapy at the time of small intestinal perforation including 2 patients who developed grade 4 neutropenia after the perforation. One of them died of infection after the perforation. The perforation rate was 15.0% in full dose chemotherapy group and 6.67% in the RDI chemotherapy group (p=0.361). The median day of perforation after initiation of chemotherapy was 21 days (range; 5-63 days). The small intestine was the most common site of perforation and 4 patients (4/5, 80%) had the ulcerative type lesions in their perforation site. CONCLUSIONS: Prior to chemotherapy, risk of GI perforation should be evaluated. We consider that small intestinal ulcerative lesion is high risk of GI perforation. The RDI chemotherapy may be an optimal therapy for patients with primary GI DLBCL with high risk. Further and larger prospective study should be required to confirm this. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1515.1515

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4418-4418

Abstract: BACKGROUND: The optimal management of relapsed or refractory aggressive B-cell lymphoma is not standardized. We previously reported the salvage chemotherapy with P-IMVP-16/CBDCA consisting of methylprednisolone (mPSL), carboplatin (CBDCA), etoposide (VP-16), ifosfamide (IFM), and methotrexate (MTX) for patients (pts) with aggressive non-Hodgkin's lymphoma who had previously received CHOP consisting of cyclophosphamide (CPA), doxorubicin (DOX), Vincristine (VCR) and prednisolone (PSL) (Sawada M; Eur J Haematol 2002). The purpose of this study is to determine the efficacy and safety of salvage chemotherapy with rituximab (R) combined with P-IMVP-16/CBDCA (R-P-IMVP-16/CBDCA) for relapsed or refractory aggressive B-cell lymphoma. PATIENTS AND METHODS: We retrospectively analyzed 66 pts with relapsed or refractory aggressive B-cell lymphoma who had received R-P-IMVP-16/CBDCA (R: 375mg/m2 on day1, mPSL: 1000mg/body on days 2-4, IFM: 1000mg/m2 on days 2-6, MTX: 30mg/m2 on day 4 and 11, VP-16: 80mg/m2 on days 2-4, and CBDCA 300mg/m2 on day 2, with granulocyte colony-stimulating factor every 21 days in 5 institutes of Gifu Hematology Study Group between July 2004 and January 2014. The pts who had responded to R-P-IMVP-16/CBDCA underwent autologous transplantation or received 3 additional R-P-IMVP-16/CBDCA cycles. Pts aged 70 or older were given 75% or less of the standard dose. All patients received R-CHOP or R-THP-COP regimen as a first-line chemotherapy. THP (pirarubicin), a derivative of DOX, is an anthracyclin with less cardiotoxicity than DOX. THP-COP has an equivalent efficacy to CHOP (Turumi H; JCRCO 2004). RESULTS: Enrolled 66 pts had a median age of 64.5 years [range 25-83] and were 65% male. The pathology of underlying lymphoma comprised diffuse large-B cell lymphoma (n=51), follicular lymphoma grade 3 (n=11), intravascular large B-cell lymphoma (n=1), primary mediastinal B cell lymphoma (n=1) and mantle cell lymphoma (n=2). The response rate [complete response (CR/CRu) plus partial response (PR)] was 60.6% (40/66), including 28 (42.4%) CR/CRu and 12 (18.2%) PR. Another 5 pts had stable disease and 21 pts progressed. Median overall survival (OS) and progression-free survival (PFS) were 47.1 months and 9.2 months, respectively. The OS rate for the 66 pts was 65.1% at 1 yr and 57.3% at 2 yr. The PFS rate for the 66 pts was 45.6% at 1 yr and 31.2% at 2 yr. The survival rate for the 40 responders was 97.4% at 1 yr and 88.1% at 2 yr, and the survival rate for the 26 non-responders was 15.0% at 1 yr (P 〈 0.001). Common toxicity criteria grade ≥ 3 drug-related adverse events included: neutropenia, anemia, thrombocytopenia and febrile neutropenia. Although the major toxicities were neutropenia and febrile neutropenia, only one DLBCL pt with common variable immunodeficiency died of sepsis related to neutropenia. Non-hematological adverse effects were predominantly mild and tolerable. CONCLUSIONS: The R-P-IMVP-16/CBDCA regimen displayed a significant activity in relapsed or refractory aggressive B-cell lymphoma, with acceptable toxicity and should be considered a candidate for combination chemotherapy. Futher clinical studies should be required. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.4418.4418

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7