62 results on '"Imaizumi, Y."'
Search Results
2. Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia-Lymphoma.
- Author
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Nakashima M, Tanaka Y, Okamura H, Kato T, Imaizumi Y, Nagai K, Miyazaki Y, and Murota H
- Subjects
- Adult, Aged, Humans, Interleukin-18, Interleukin-2, Leukocytes, Mononuclear, Immunotherapy, Antibodies, Monoclonal, Leukemia-Lymphoma, Adult T-Cell therapy, Human T-lymphotropic virus 1
- Abstract
γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4
+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.- Published
- 2024
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3. Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma.
- Author
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Kameda T, Kataoka K, Kamiunten A, Hidaka M, Miyoshi H, Nakano N, Nosaka K, Yoshimitsu M, Yasunaga JI, Kogure Y, Shide K, Miyahara M, Sakamoto T, Akizuki K, Hidaka T, Kubuki Y, Koya J, Kawano N, Yamashita K, Kawano H, Toyama T, Maeda K, Marutsuka K, Imaizumi Y, Kato K, Sugio T, Tokunaga M, Tashiro Y, Takaori-Kondo A, Miyazaki Y, Akashi K, Ishitsuka K, Matsuoka M, Ohshima K, Watanabe T, Kitanaka A, Utsunomiya A, Ogawa S, and Shimoda K
- Subjects
- Adult, Humans, Prognosis, Receptors, CCR7, Retrospective Studies, Leukemia-Lymphoma, Adult T-Cell genetics, Leukemia-Lymphoma, Adult T-Cell therapy, Hematopoietic Stem Cell Transplantation, Lymphoma
- Abstract
The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).
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- 2023
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4. Landscape of immunoglobulin heavy chain γ gene class switch recombination in patients with adult T-cell leukemia-lymphoma.
- Author
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Hiramatsu H, Nosaka K, Kusumoto S, Nakano N, Choi I, Yoshimitsu M, Imaizumi Y, Hidaka M, Sasaki H, Makiyama J, Ohtsuka E, Jo T, Ogata M, Ito A, Yonekura K, Tatetsu H, Kato T, Kawakita T, Suehiro Y, Ishitsuka K, Iida S, Matsutani T, Nishikawa H, Utsunomiya A, Ueda R, and Ishida T
- Subjects
- Humans, Immunoglobulin Class Switching genetics, Immunoglobulin Heavy Chains genetics, Immunoglobulin gamma-Chains genetics, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Leukemia-Lymphoma, Adult T-Cell genetics
- Published
- 2023
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5. Validation of the iATL-PI prognostic index in therapeutic decision-making for patients with smoldering and chronic ATL: a multicenter study.
- Author
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Imaizumi Y, Iwanaga M, Nosaka K, Ishitsuka K, Ishizawa K, Ito S, Amano M, Ishida T, Uike N, Utsunomiya A, Ohshima K, Tanaka J, Tokura Y, Tobinai K, Watanabe T, Uchimaru K, and Tsukasaki K
- Subjects
- Adult, Humans, Prognosis, Follow-Up Studies, Receptors, Interleukin-2, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell therapy, Leukemia-Lymphoma, Adult T-Cell pathology, Lymphoma
- Abstract
Adult T cell leukemia-lymphoma (ATL) is clinically heterogeneous and is classified into four subtypes: acute, lymphoma, chronic, and smoldering. Recently, a new prognostic index based on the value of soluble interleukin-2 receptor, denoted the "iATL-PI," has been proposed for patients with smoldering and chronic ATL. To evaluate the effectiveness of the iATL-PI, we re-analyzed our previously published data on 176 patients with smoldering or chronic ATL (76 smoldering, 100 chronic) diagnosed between 2010 and 2011, as well data from the subsequent follow-up study on prognosis between 2016 and 2017. The proportions for the low-, intermediate-, and high-risk iATL-PI groups at the time of ATL diagnosis were 44.7%, 48.7%, and 5% for smoldering ATL; 6.3%, 71.9%, and 21.9% for favorable chronic ATL; and 5.9%, 27.9%, and 66.2% for unfavorable chronic ATL, respectively. The survival of patients with smoldering or chronic ATL as a whole was significantly stratified according to the three iATL-PI groups. Most patients with unfavorable chronic ATL in the low iATL-PI risk group had indolent clinical courses. Our results showed that iATL may become a useful tool to predict the prognosis of smoldering and chronic ATL, which have diverse clinical courses., (© 2022. Japanese Society of Hematology.)
- Published
- 2023
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6. Alvocidib inhibits IRF4 expression via super-enhancer suppression and adult T-cell leukemia/lymphoma cell growth.
- Author
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Sakamoto H, Ando K, Imaizumi Y, Mishima H, Kinoshita A, Kobayashi Y, Kitanosono H, Kato T, Sawayama Y, Sato S, Hata T, Nakashima M, Yoshiura KI, and Miyazaki Y
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinases antagonists & inhibitors, Genes, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, Leukemia-Lymphoma, Adult T-Cell drug therapy, Leukemia-Lymphoma, Adult T-Cell genetics, Leukemia-Lymphoma, Adult T-Cell pathology, Antineoplastic Agents pharmacology
- Abstract
Adult T-cell leukemia/lymphoma (ATL) is an intractable hematological malignancy with extremely poor prognosis. Recent studies have revealed that super-enhancers (SE) play important roles in controlling tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases including ATL. Cyclin-dependent protein kinase (CDK) 9 is a component of a complex comprising transcription factors (TFs) that bind the SE region. Alvocidib is a CDK9 inhibitor that exerts antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressing SE-mediated, tumor-specific gene expression. The present study demonstrated that alvocidib inhibited the proliferation of ATL cell lines and tumor cells from patients with ATL. RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) disclosed that SE regulated IRF4 in the ATL cell lines. Previous studies showed that IRF4 suppression inhibited ATL cell proliferation. Hence, IRF4 is a putative alvocidib target in ATL therapy. The present study revealed that SE-mediated IRF4 downregulation is a possible mechanism by which alvocidib inhibits ATL proliferation. Alvocidib also suppressed ATL in a mouse xenograft model. Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2022
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7. Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma.
- Author
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Tanaka N, Mori S, Kiyotani K, Ota Y, Gotoh O, Kusumoto S, Nakano N, Suehiro Y, Ito A, Choi I, Ohtsuka E, Hidaka M, Nosaka K, Yoshimitsu M, Imaizumi Y, Iida S, Utsunomiya A, Noda T, Nishikawa H, Ueda R, and Ishida T
- Subjects
- Adult, Antibodies, Monoclonal, Humanized, CD28 Antigens, DNA Copy Number Variations, Genomics, Homozygote, Humans, Nucleotides, Receptors, CCR7, Sequence Deletion, Treatment Outcome, Leukemia-Lymphoma, Adult T-Cell drug therapy, Leukemia-Lymphoma, Adult T-Cell genetics, Leukemia-Lymphoma, Adult T-Cell pathology, Lymphoma
- Abstract
In order to identify genomic biomarkers for the outcome of mogamulizumab-containing treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNV)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P=0.024, and CR rate 71%, 40/56; P=0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNV/indels or copy number variations (CNV) such as homozygous deletion; CD28 alterations included SNV, CNV such as amplification, or fusion; CD274 alterations included CNV such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS) (hazard ratio [HR]: 2.330, 95% confidence interval [CI]: 1.183-4.589; HR: 3.191, 95% CI: 1.287- 7.911; HR: 3.301, 95% CI: 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR: 0.286, 95% CI: 0.087-0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR: 2.467, 95% CI: 1.197-5.085; HR: 0.155, 95% CI: 0.031-0.778; HR: 14.393, 95% CI: 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.
- Published
- 2022
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8. Oral histone deacetylase inhibitor tucidinostat (HBI-8000) in patients with relapsed or refractory adult T-cell leukemia/lymphoma: Phase IIb results.
- Author
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Utsunomiya A, Izutsu K, Jo T, Yoshida S, Tsukasaki K, Ando K, Choi I, Imaizumi Y, Kato K, Kurosawa M, Kusumoto S, Miyagi T, Ohtsuka E, Sasaki O, Shibayama H, Shimoda K, Takamatsu Y, Takano K, Yonekura K, Makita S, Taguchi J, Gillings M, Onogi H, and Tobinai K
- Subjects
- Adult, Benzamides, Histone Deacetylase Inhibitors adverse effects, Humans, Prospective Studies, Pyridines, Recurrence, Treatment Outcome, Leukemia-Lymphoma, Adult T-Cell drug therapy, Lymphoma, Follicular drug therapy
- Abstract
This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2022
- Full Text
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9. RAISING is a high-performance method for identifying random transgene integration sites.
- Author
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Wada Y, Sato T, Hasegawa H, Matsudaira T, Nao N, Coler-Reilly ALG, Tasaka T, Yamauchi S, Okagawa T, Momose H, Tanio M, Kuramitsu M, Sasaki D, Matsumoto N, Yagishita N, Yamauchi J, Araya N, Tanabe K, Yamagishi M, Nakashima M, Nakahata S, Iha H, Ogata M, Muramatsu M, Imaizumi Y, Uchimaru K, Miyazaki Y, Konnai S, Yanagihara K, Morishita K, Watanabe T, Yamano Y, and Saito M
- Subjects
- Adult, High-Throughput Nucleotide Sequencing, Humans, Transgenes, Virus Integration genetics, Human T-lymphotropic virus 1 genetics, Leukemia-Lymphoma, Adult T-Cell genetics, Leukemia-Lymphoma, Adult T-Cell pathology, Leukemia-Lymphoma, Adult T-Cell therapy
- Abstract
Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking clonality via the detection of transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive high throughput sequencing. We analyzed samples from 688 individuals infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL) to model our method. We defined a clonality value identifying ATL patients with 100% sensitivity and 94.8% specificity, and our longitudinal analysis also demonstrates the usefulness of ATL risk assessment. Future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector., (© 2022. The Author(s).)
- Published
- 2022
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10. Nationwide Hospital-Based Survey of Adult T-Cell Leukemia/Lymphoma in Japan.
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Kato T, Imaizumi Y, and Miyazaki Y
- Subjects
- Adult, Aged, Hospitals, Humans, Japan epidemiology, Prognosis, Leukemia-Lymphoma, Adult T-Cell epidemiology, Lymphoma
- Abstract
Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of patients with ATL diagnosed in the 1980s. This article highlighted the classification and prognosis of ATL based on different surveys and focused on the comparison of data derived from the available surveys. The 11th nationwide hospital-based survey was conducted in patients with ATL diagnosed in 2010-2011 using the same method as that used in the 1980s survey. The median age of disease onset was 68 years, which was increased compared with previous surveys. While median survival of patients with the acute and lymphoma types had not improved much since the 1980s, the 4-year survival rate was higher. Little improvement in the prognosis was observed for the chronic and smoldering types. The 12th nationwide survey of patients with ATL diagnosed in 2012-2013 also showed an increase in age at onset. Further epidemiological research that includes more cases is needed to deepen our understanding of the actual state of treatment and prognosis of this disease.
- Published
- 2022
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11. Whole-genome landscape of adult T-cell leukemia/lymphoma.
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Kogure Y, Kameda T, Koya J, Yoshimitsu M, Nosaka K, Yasunaga JI, Imaizumi Y, Watanabe M, Saito Y, Ito Y, McClure MB, Tabata M, Shingaki S, Yoshifuji K, Chiba K, Okada A, Kakiuchi N, Nannya Y, Kamiunten A, Tahira Y, Akizuki K, Sekine M, Shide K, Hidaka T, Kubuki Y, Kitanaka A, Hidaka M, Nakano N, Utsunomiya A, Sica RA, Acuna-Villaorduna A, Janakiram M, Shah U, Ramos JC, Shibata T, Takeuchi K, Takaori-Kondo A, Miyazaki Y, Matsuoka M, Ishitsuka K, Shiraishi Y, Miyano S, Ogawa S, Ye BH, Shimoda K, and Kataoka K
- Subjects
- Animals, DNA Copy Number Variations, Female, Genome, Human, Humans, Leukemia-Lymphoma, Adult T-Cell genetics, Mice, Mice, Inbred C57BL, Prognosis, Survival Rate, Exome Sequencing, Ataxin-1 genetics, Biomarkers, Tumor genetics, Gene Expression Regulation, Neoplastic, Leukemia-Lymphoma, Adult T-Cell pathology, Mutation, Proto-Oncogene Proteins c-rel genetics, Repressor Proteins genetics
- Abstract
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3'-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery., (© 2022 by The American Society of Hematology.)
- Published
- 2022
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12. Clinical significance of the immunoglobulin G heavy-chain repertoire in peripheral blood mononuclear cells of adult T-cell leukaemia-lymphoma patients receiving mogamulizumab.
- Author
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Nosaka K, Kusumoto S, Nakano N, Choi I, Yoshimitsu M, Imaizumi Y, Hidaka M, Sasaki H, Makiyama J, Ohtsuka E, Jo T, Ogata M, Ito A, Yonekura K, Tatetsu H, Kato T, Kawakita T, Suehiro Y, Ishitsuka K, Iida S, Matsutani T, Utsunomiya A, Ueda R, and Ishida T
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Female, Genetic Variation, Humans, Leukemia-Lymphoma, Adult T-Cell blood, Leukemia-Lymphoma, Adult T-Cell drug therapy, Leukemia-Lymphoma, Adult T-Cell mortality, Male, Middle Aged, Prognosis, Proportional Hazards Models, Survival Analysis, Treatment Outcome, Biomarkers, Tumor, Circulating Tumor DNA, Immunoglobulin G genetics, Immunoglobulin Heavy Chains genetics, Leukemia-Lymphoma, Adult T-Cell genetics, Leukocytes, Mononuclear metabolism
- Abstract
'Monitoring of immune responses following mogamulizumab-containing treatment in patients with adult T-cell leukaemia-lymphoma (ATL)' (MIMOGA) is a multicentre prospective clinical study (UMIN000008696). In the MIMOGA study, we found that a lower percentage of CD2
- CD19+ B cells in peripheral blood mononuclear cells (PBMC) was a significant unfavourable prognostic factor for overall survival (OS). Accordingly, we then analysed the immunoglobulin G (IgG) heavy-chain repertoire in PBMC by high-throughput sequencing. Of the 101 patients enrolled in the MIMOGA study, for 81 a sufficient amount of PBMC RNA was available for repertoire sequencing analysis. Peripheral IgG B cells in patients with ATL had a restricted repertoire relative to those in healthy individuals. There was a significant positive correlation between the Shannon-Weaver diversity index (SWDI) for the IgG repertoire and proportions of B cells in the PBMC of the patients. Multivariate analysis identified two variables significantly affecting OS: a higher serum soluble interleukin-2 receptor level, and a lower SWDI for the IgG repertoire [hazard ratio, 2·124; 95% confidence interval, 1·114-4·049; n = 44]. The present study documents the importance of humoral immune responses in patients receiving mogamulizumab-containing treatment. Further investigation of strategies to enhance humoral immune responses in patients with ATL is warranted., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2022
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13. TAS-116 (pimitespib), a heat shock protein 90 inhibitor, shows efficacy in preclinical models of adult T-cell leukemia.
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Ikebe E, Shimosaki S, Hasegawa H, Iha H, Tsukamoto Y, Wang Y, Sasaki D, Imaizumi Y, Miyazaki Y, Yanagihara K, Hamaguchi I, and Morishita K
- Subjects
- Animals, Antineoplastic Agents pharmacology, Benzamides pharmacology, Cell Cycle drug effects, Cell Survival drug effects, Cells, Cultured, Humans, Mice, NF-kappa B metabolism, Pyrazoles pharmacology, Signal Transduction drug effects, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Benzamides therapeutic use, HSP90 Heat-Shock Proteins antagonists & inhibitors, Leukemia-Lymphoma, Adult T-Cell drug therapy, Pyrazoles therapeutic use
- Abstract
Adult T-cell leukemia/lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-cell leukemia virus type 1 infection, for which there is an urgent need for more effective therapeutic options. The molecular chaperone heat shock protein 90 (HSP90) plays a crucial role in nuclear factor-κB (NF-κB)-mediated antiapoptosis in ATL cells, and HSP90 inhibitors are new candidate therapeutics for ATL. Accordingly, we investigated the anti-ATL effects of a novel oral HSP90 inhibitor, TAS-116 (pimitespib), and the mechanisms involved in ex vivo and in vivo preclinical models. TAS-116 achieved IC
50 values of less than 0.5 μmol/L in 10 ATL-related cell lines and less than 1 μmol/L in primary peripheral blood cells of nine ATL patients; no toxicity was observed toward CD4+ lymphocytes from healthy donors, indicating the safety of this agent. Given orally, TAS-116 also showed significant inhibitory effects against tumor cell growth in ATL cell-xenografted mice. Furthermore, gene expression profiling of TAS-116-treated Tax-positive or -negative cell lines and primary ATL cells using DNA microarray and multiple pathway analysis revealed the significant downregulation of the NF-κB pathway in Tax-positive cells and cell-cycle arrest in Tax-negative cells and primary ATL cells. TAS-116 suppressed the activator protein-1 and tumor necrosis factor pathways in all examined cells. These findings strongly indicate the efficacy of TAS-116, regardless of the stage of ATL progression, and its potential application as a novel clinical anti-ATL therapeutic agent., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)- Published
- 2022
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14. Epidemiology of adult T-cell leukemia-lymphoma in Japan: An updated analysis, 2012-2013.
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Ito S, Iwanaga M, Nosaka K, Imaizumi Y, Ishitsuka K, Amano M, Utsunomiya A, Tokura Y, Watanabe T, Uchimaru K, and Tsukasaki K
- Subjects
- Adult, Age Distribution, Aged, Aged, 80 and over, Databases, Factual statistics & numerical data, Emigration and Immigration statistics & numerical data, Endemic Diseases, Female, HTLV-I Infections epidemiology, Health Surveys, Human T-lymphotropic virus 1, Humans, Japan epidemiology, Male, Middle Aged, Registries statistics & numerical data, Retrospective Studies, Sex Distribution, Time Factors, Leukemia-Lymphoma, Adult T-Cell epidemiology
- Abstract
Adult T-cell leukemia-lymphoma (ATL) is a T-cell malignancy that is endemic to Japan. In this latest nationwide study of ATL, we collected the data from 4 nationwide registries of patients diagnosed in 2012-2013; the Hematology Blood Disease, the Skin Cancer Society, the Hospital-Based Cancer Registries, and information from the hospitals that participated in the Japanese nationwide survey of ATL in 2010-2011. In the present study, 2614 patients with ATL were diagnosed based on the registries, and 117 departments registered 1042 patients. Among these patients, 984 were eligible for analysis. The median age at diagnosis was 69 y. A larger proportion of patients with ATL older than 70 y was diagnosed with the lymphoma subtype, and more than half of the patients with ATL in the metropolitan areas were born in the human T-cell leukemia virus type I (HTLV-1)-endemic areas of Kyushu/Okinawa, which are almost identical to the findings in our 2010-2011 study. Additionally, we identified that patients with ATL migrated from the endemic areas for HTLV-1 to the non-endemic metropolitan areas. The present study was able to reduce the burden of searching each hospital and to update the clinico-epidemiological characteristics of a large number of patients with ATL in Japan, suggesting the usefulness and feasibility of the novel data collection method. The establishment of a more sophisticated database management system for ATL is necessary for future continuous surveys., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2021
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15. Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma with HTLV-1-associated myelopathy.
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Sakamoto H, Itonaga H, Sawayama Y, Kojima A, Chiwata M, Fujioka M, Kitanosono H, Horai M, Miyazaki T, Shiraishi H, Imaizumi Y, Yoshida S, Hata T, Yamano Y, and Miyazaki Y
- Subjects
- Human T-lymphotropic virus 1 isolation & purification, Humans, Male, Middle Aged, Spinal Cord Diseases virology, Transplantation, Homologous, Treatment Outcome, HTLV-I Infections complications, Hematopoietic Stem Cell Transplantation, Leukemia-Lymphoma, Adult T-Cell complications, Leukemia-Lymphoma, Adult T-Cell therapy, Spinal Cord Diseases complications
- Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for adult T-cell leukemia/lymphoma (ATL), but comorbidities increase transplant-related mortality. Here we report the outcome of allo-HSCT in a patient with ATL with human T-cell leukemia virus type I (HTLV-1)-associated myelopathy-tropical spastic paraparesis (HAM/TSP). A 48-year-old man was diagnosed with HAM/TSP and started prednisolone therapy. Ten years later, he developed lymphoma-type ATL. At the diagnosis of ATL, Osame's Motor Disability Score (OMDS) was 4. When prednisolone was gradually tapered and stopped following chemotherapy for ATL, HAM/TSP symptoms recurred (OMDS 7). Bone marrow transplantation from a human leukocyte antigen allele 8/8 matched unrelated donor was performed while ATL was in partial remission. Neutrophil engraftment with complete donor chimerism was achieved on day 19 after allo-HSCT. Mild gait improvement (OMDS 5) was observed on day 30. Although ATL relapsed on day 275, progression of HAM/TSP symptoms was not observed. Furthermore, there was no clear progression of HAM/TSP symptoms after donor lymphocyte infusions. The outcome of this case suggests that ATL patients with HAM/TSP tolerate allo-HSCT and donor lymphocyte infusions.
- Published
- 2021
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16. [The results of a nationwide survey on patients with adult T-cell leukemia-lymphoma].
- Author
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Imaizumi Y
- Subjects
- Adult, Humans, Japan epidemiology, Prognosis, Receptors, Interleukin-2, Survival Rate, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell epidemiology, Leukemia-Lymphoma, Adult T-Cell therapy
- Abstract
Adult T-cell leukemia-lymphoma (ATL) is a rare disease, and the nationwide surveys conducted in Japan have played an important role in improving our understanding of the clinical features and prognosis of this disease. The diagnostic criteria of clinical subtypes have been proposed based on the surveys conducted on patients with ATL who were diagnosed in the 1980s; the current treatment guideline in Japan is based on this classification of ATL subtypes. In the survey for patients diagnosed between 2000 and 2009, the usefulness of the clinical subtypes was confirmed, and soluble interleukin-2 receptor was identified as a new prognostic factor for chronic- and smoldering-type ATL. We conducted another survey for patients who were diagnosed in 2010 and 2011. The age at diagnosis was higher than that reported in previous trials, and the median patient age at diagnosis was 68 years in the study. The 4-year survival rate was better than that in previous studies on acute- and lymphoma-type disease; however, the prognosis has not improved in chronic- and smoldering-type disease. Further nationwide surveys are expected to improve the treatment strategies for ATL.
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- 2021
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17. Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.
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Imaizumi Y, Iwanaga M, Nosaka K, Ishitsuka K, Ishizawa K, Ito S, Amano M, Ishida T, Uike N, Utsunomiya A, Ohshima K, Tanaka J, Tokura Y, Tobinai K, Watanabe T, Uchimaru K, and Tsukasaki K
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Cause of Death, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Female, Health Care Surveys statistics & numerical data, Hospitals statistics & numerical data, Humans, Japan epidemiology, Leukemia-Lymphoma, Adult T-Cell blood, Leukemia-Lymphoma, Adult T-Cell classification, Male, Middle Aged, Nitrosourea Compounds administration & dosage, Prednisone administration & dosage, Prognosis, Retrospective Studies, Survival Rate, Vincristine administration & dosage, Vindesine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia-Lymphoma, Adult T-Cell mortality, Leukemia-Lymphoma, Adult T-Cell therapy
- Abstract
Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2020
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18. Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study.
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Yonekura K, Kusumoto S, Choi I, Nakano N, Ito A, Suehiro Y, Imaizumi Y, Yoshimitsu M, Nosaka K, Ohtsuka E, Hidaka M, Jo T, Sasaki H, Moriuchi Y, Ogata M, Tatetsu H, Ishitsuka K, Miyazaki Y, Ueda R, Utsunomiya A, and Ishida T
- Subjects
- Adult, Antibodies, Monoclonal, Humanized, Humans, Leukocytes, Mononuclear, T-Lymphocytes, Cytotoxic, Leukemia-Lymphoma, Adult T-Cell drug therapy
- Abstract
Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696). Mogamulizumab-naive patients were enrolled (n = 102), of whom 101 received mogamulizumab-containing treatment (68 acute, 18 lymphoma, 12 chronic, and 3 smoldering subtypes). At enrollment, there was a significant inverse correlation between serum soluble interleukin-2 receptor (sIL-2R) levels and percentages of Tax-specific cytotoxic T lymphocytes (Tax-CTLs) in the entire lymphocyte population or in the CD8+ T cell subset, but there was not a correlation with cytomegalovirus pp65-specific cytotoxic T lymphocytes (CMV-CTLs). The overall response rate was 65%, and median progression-free survival and overall survival (OS) were 7.4 and 16.0 months, respectively. A higher percentage of Tax-CTLs, but not CMV-CTLs, within the entire lymphocyte population or in the CD8+ T cell subset was significantly associated with longer survival. Multivariate analysis identified the clinical subtype (acute or lymphoma type), a higher sIL-2R level, and a lower percentage of CD2-CD19+ B cells in peripheral blood mononuclear cells as significant independent unfavorable prognostic factors for OS. This indicates that a higher percentage of B cells might reflect some aspect of a favorable immune status leading to a good outcome with mogamulizumab treatment. In conclusion, the MIMOGA study has demonstrated that mogamulizumab exerts clinically meaningful antitumor activity in ATL. The patient's immunological status before mogamulizumab was significantly associated with treatment outcome. Further time series immunological analyses, in addition to comprehensive genomic analyses, are warranted., (© 2020 by The American Society of Hematology.)
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- 2020
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19. A high-throughput detection method for the clonality of Human T-cell leukemia virus type-1-infected cells in vivo.
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Saito M, Hasegawa H, Yamauchi S, Nakagawa S, Sasaki D, Nao N, Tanio M, Wada Y, Matsudaira T, Momose H, Kuramitsu M, Yamagishi M, Nakashima M, Nakahata S, Iha H, Ogata M, Imaizumi Y, Uchimaru K, Morishita K, Watanabe T, Miyazaki Y, and Yanagihara K
- Subjects
- High-Throughput Nucleotide Sequencing methods, Humans, Clone Cells, HTLV-I Infections diagnosis, Human T-lymphotropic virus 1 genetics, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell virology, Nucleic Acid Amplification Techniques methods
- Abstract
Approximately 10-20 million of Human T-cell leukemia virus type-1 (HTLV-1)-infected carriers have been previously reported, and approximately 5% of these carriers develop adult T-cell leukemia/lymphoma (ATL) with a characteristic poor prognosis. In Japan, Southern blotting has long been routinely performed for detection of clonally expanded ATL cells in vivo, and as a confirmatory diagnostic test for ATL. However, alternative methods to Southern blotting, such as sensitive, quantitative, and rapid analytical methods, are currently required in clinical practice. In this study, we developed a high-throughput method called rapid amplification of integration site (RAIS) that could amplify HTLV-1-integrated fragments within 4 h and detect the integration sites in > 0.16% of infected cells. Furthermore, we established a novel quantification method for HTLV-1 clonality using Sanger sequencing with RAIS products, and the validity of the quantification method was confirmed by comparing it with next-generation sequencing in terms of the clonality. Thus, we believe that RAIS has a high potential for use as an alternative routine molecular confirmatory test for the clonality analysis of HTLV-1-infected cells.
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- 2020
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20. Treatment with mogamulizumab or lenalidomide for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience.
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Sakamoto H, Itonaga H, Sawayama Y, Furumoto T, Fujioka M, Chiwata M, Toriyama E, Kasai S, Nakashima J, Horai M, Kato T, Sato S, Ando K, Taguchi J, Imaizumi Y, Yoshida S, Hata T, Moriuchi Y, and Miyazaki Y
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- Adult, Aged, Female, Follow-Up Studies, Humans, Leukemia-Lymphoma, Adult T-Cell pathology, Leukemia-Lymphoma, Adult T-Cell therapy, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local therapy, Prognosis, Retrospective Studies, Salvage Therapy, Survival Rate, Transplantation, Homologous, Angiogenesis Inhibitors therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Hematopoietic Stem Cell Transplantation mortality, Lenalidomide therapeutic use, Leukemia-Lymphoma, Adult T-Cell drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
Mogamulizumab (Mog) and lenalidomide (Len) are new therapeutic candidates for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we retrospectively analyzed 12 patients who received Mog or Len monotherapy for relapsed ATL after allo-HSCT. Eight and three patients received Mog and Len, respectively. The remaining patient received Mog for the first relapse and Len for the third relapse. A complete response was achieved by three and two patients who received Mog and Len, respectively, two and one of whom remained alive with a complete response for more than 20 months. In terms of adverse events, the emergence or progression of graft-versus-host disease was observed in three out of four patients treated with Len and in none of the patients treated with Mog. The development or progression of cytomegalovirus reactivation was detected in four out of eight patients treated with Mog and in none of those treated with Len. The present results suggest that Mog and Len would be promising treatment options for relapsed ATL after allo-HSCT and need to be selected based on adverse event profiles., (© 2020 John Wiley & Sons Ltd.)
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- 2020
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21. [Composite adult T-cell leukemia/lymphoma and Epstein-Barr virus-positive diffuse large B-cell lymphoma].
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Sakamoto H, Imaizumi Y, Niino D, Takeuchi M, Matsui K, Horai M, Sato S, Akazawa Y, Ando K, Sawayama Y, Hata T, Ohshima K, and Miyazaki Y
- Subjects
- Adult, Epstein-Barr Virus Infections, Female, Herpesvirus 4, Human, Human T-lymphotropic virus 1, Humans, Leukemia-Lymphoma, Adult T-Cell, Lymphoma, Large B-Cell, Diffuse
- Abstract
Human T-cell leukemia virus type I (HTLV-1) infection and adult T-cell leukemia-lymphoma (ATL) have been shown to cause immunodeficiency. However, only a few cases have been reported on the development of Epstein-Barr virus positive-diffuse large B-cell lymphoma (EBV-DLBCL) in HTLV-1 carriers or in patients with ATL. Here we report a case of a female HTLV-1 carrier who developed cytomegalovirus (CMV) retinitis. During the CMV retinitis treatment, she developed a liver tumor. The diagnosis of composite ATL and EBV-DLBCL was made by tumor biopsy. The patient also suffered from pulmonary cryptococcosis and invasive pulmonary aspergillosis at the time of chemotherapy initiation. She had repeated CMV antigenemia and bacterial sepsis during the course of chemotherapy, and she died of bacterial sepsis. HTLV-1 carriers who are complicated with opportunistic infections should be carefully observed not only for ATL development but also for the development of EBV-DLBCL and associated infectious complications.
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- 2020
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22. Clinical features at transformation in adult T-cell leukemia-lymphoma with smoldering and chronic types.
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Taniguchi H, Imaizumi Y, Takasaki Y, Nakashima J, Kato T, Itonaga H, Sato S, Sawayama Y, Ando K, Hasegawa H, Hata T, Moriuchi Y, Tsukasaki K, and Miyazaki Y
- Subjects
- Adult, Aged, Chronic Disease, Disease-Free Survival, Female, Humans, Male, Middle Aged, Retrospective Studies, Survival Rate, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Leukemia-Lymphoma, Adult T-Cell metabolism, Leukemia-Lymphoma, Adult T-Cell mortality, Leukemia-Lymphoma, Adult T-Cell pathology
- Abstract
Watchful waiting (WW) is among the treatment options indicated for patients with indolent adult T-cell leukemia-lymphoma (ATL). However, we previously showed that the long-term prognosis of patients with smoldering and chronic ATL is often worse than expected, with many undergoing transformation to aggressive ATL. To identify clinical features associated with transformation of smoldering/chronic ATL, we retrospectively analyzed the clinical features of 44 patients (14 smoldering and 30 chronic) who experienced transformation during WW. An elevated lactate dehydrogenase (LDH) value was most often observed (n = 30) at the time of transformation, especially in the chronic type (n = 24). Major organ involvement, lymphadenopathy, and hypercalcemia were shown to be associated with transformation in transformed patients without elevated LDH. The median overall survival time after transformation was only 7.8 months, and the prognosis was poor after transformation in those fulfilling the criteria of acute type, similar to that of de novo aggressive ATL. Laboratory data, such as LDH, and clinical signs including exacerbation of performance status, skin lesions, and lymphadenopathy should all be monitored during WW to ensure appropriate timing of chemotherapy initiation. Identification of optimal predictive markers for transformation and new therapeutic options is warranted to improve outcomes in indolent ATL.
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- 2019
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23. Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report.
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Cook LB, Fuji S, Hermine O, Bazarbachi A, Ramos JC, Ratner L, Horwitz S, Fields P, Tanase A, Bumbea H, Cwynarski K, Taylor G, Waldmann TA, Bittencourt A, Marcais A, Suarez F, Sibon D, Phillips A, Lunning M, Farid R, Imaizumi Y, Choi I, Ishida T, Ishitsuka K, Fukushima T, Uchimaru K, Takaori-Kondo A, Tokura Y, Utsunomiya A, Matsuoka M, Tsukasaki K, and Watanabe T
- Subjects
- Antineoplastic Agents adverse effects, Central Nervous System Neoplasms mortality, Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms virology, Consensus, Human T-lymphotropic virus 1 pathogenicity, Humans, Leukemia-Lymphoma, Adult T-Cell mortality, Leukemia-Lymphoma, Adult T-Cell pathology, Leukemia-Lymphoma, Adult T-Cell virology, Risk Factors, Skin Neoplasms mortality, Skin Neoplasms pathology, Skin Neoplasms virology, Transplantation, Homologous, Treatment Outcome, Antineoplastic Agents therapeutic use, Central Nervous System Neoplasms therapy, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Leukemia-Lymphoma, Adult T-Cell therapy, Medical Oncology standards, Skin Neoplasms therapy
- Abstract
Purpose: Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches., Methods: Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology-Human T-Lymphotropic Virus and Related Retroviruses-in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents., Results: As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement)., Conclusion: This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL.
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- 2019
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24. Clinical factors to predict outcome following mogamulizumab in adult T-cell leukemia-lymphoma.
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Nakashima J, Imaizumi Y, Taniguchi H, Ando K, Iwanaga M, Itonaga H, Sato S, Sawayama Y, Hata T, Yoshida S, Moriuchi Y, and Miyazaki Y
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Disease-Free Survival, Female, Humans, Male, Middle Aged, Risk Factors, Survival Rate, Antibodies, Monoclonal, Humanized administration & dosage, Leukemia-Lymphoma, Adult T-Cell blood, Leukemia-Lymphoma, Adult T-Cell drug therapy, Leukemia-Lymphoma, Adult T-Cell mortality
- Abstract
Adult T-cell leukemia-lymphoma (ATL) is a distinct T-cell malignancy caused by human T-cell leukemia virus type-1; the prognosis is very poor. Mogamulizumab (Moga), an antibody drug for CC chemokine receptor type 4, has been introduced for the treatment of ATL. However, the prognosis of relapsed or refractory ATL remains poor and the characteristics of patients who derive clinical benefit from treatment with Moga remain poorly understood. We analyzed the associations of clinical factors with the outcome after Moga treatment. Forty-five patients treated with Moga monotherapy were evaluated. The median age of the patients was 69 years, and 40% were female. The median overall survival (OS) time was 17.6 months and the 2-year OS rate was 43.2%. Number of prior therapies and response to prior therapy were predictive clinical features in univariate analysis for OS. Performance status, corrected serum calcium level, serum lactate dehydrogenase level, Japan Clinical Oncology Group-prognostic index (PI), and simplified ATL-PI at Moga treatment were also associated with the prognosis after Moga monotherapy. Improved understanding of the clinical factors predicting the prognosis after Moga may contribute to improved treatment strategies for ATL.
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- 2018
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25. EPOCH regimen as salvage therapy for adult T-cell leukemia-lymphoma.
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Toriyama E, Imaizumi Y, Taniguchi H, Taguchi J, Nakashima J, Itonaga H, Sato S, Ando K, Sawayama Y, Hata T, Fukushima T, and Miyazaki Y
- Subjects
- Adult, Aged, Allografts, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Etoposide administration & dosage, Female, Humans, Leukemia-Lymphoma, Adult T-Cell mortality, Male, Middle Aged, Prednisone administration & dosage, Retrospective Studies, Survival Rate, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia-Lymphoma, Adult T-Cell therapy, Salvage Therapy
- Abstract
Adult T-cell leukemia-lymphoma (ATL) is an intractable hematopoietic malignancy with a very poor prognosis. Although improved responses have been achieved through intensive chemotherapy in newly diagnosed patients with aggressive ATL, most patients suffer from relapse or disease recurrence, and an effective salvage therapy, especially for candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT), is yet to be established. The efficacy of the EPOCH regimen has been reported for several lymphoid malignancies; however, its efficacy for ATL has not been sufficiently evaluated. Here, we report results of a study of the EPOCH regimen as a salvage therapy for ATL. We retrospectively analyzed patients with relapsed or refractory ATL treated in our institution, with EPOCH as a first salvage therapy. Fourteen patients with a median age of 58 years were analyzed, among whom eight achieved a response, including a complete response in one patient and partial responses in seven. Seven patients underwent allo-HSCT after EPOCH therapy; however, the median overall survival (OS) could not be determined, whereas OS at 2 years after allo-HSCT was estimated to be 85.7%. These results suggest that EPOCH is an option for salvage therapy in patients with ATL, including candidates for allo-HSCT.
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- 2018
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26. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma.
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Kataoka K, Iwanaga M, Yasunaga JI, Nagata Y, Kitanaka A, Kameda T, Yoshimitsu M, Shiraishi Y, Sato-Otsubo A, Sanada M, Chiba K, Tanaka H, Ochi Y, Aoki K, Suzuki H, Shiozawa Y, Yoshizato T, Sato Y, Yoshida K, Nosaka K, Hishizawa M, Itonaga H, Imaizumi Y, Munakata W, Shide K, Kubuki Y, Hidaka T, Nakamaki T, Ishiyama K, Miyawaki S, Ishii R, Nureki O, Tobinai K, Miyazaki Y, Takaori-Kondo A, Shibata T, Miyano S, Ishitsuka K, Utsunomiya A, Shimoda K, Matsuoka M, Watanabe T, and Ogawa S
- Subjects
- Abnormal Karyotype, Aged, Epigenesis, Genetic, Female, Gene Dosage, Humans, Interferon Regulatory Factors genetics, Male, Middle Aged, Models, Molecular, Polymorphism, Single Nucleotide, Prognosis, STAT3 Transcription Factor genetics, Gene Expression Regulation, Leukemic, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell genetics, Mutation
- Abstract
Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients., (© 2018 by The American Society of Hematology.)
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- 2018
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27. Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey.
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Nosaka K, Iwanaga M, Imaizumi Y, Ishitsuka K, Ishizawa K, Ishida Y, Amano M, Ishida T, Uike N, Utsunomiya A, Ohshima K, Kawai K, Tanaka J, Tokura Y, Tobinai K, Watanabe T, Uchimaru K, and Tsukasaki K
- Subjects
- Adult, Aged, Female, Humans, Japan epidemiology, Male, Middle Aged, Surveys and Questionnaires, Leukemia-Lymphoma, Adult T-Cell epidemiology, Leukemia-Lymphoma, Adult T-Cell pathology
- Abstract
Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital-based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60-75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu-Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one-third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV-1 carrier status are needed., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2017
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28. Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies.
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Ishida T, Utsunomiya A, Jo T, Yamamoto K, Kato K, Yoshida S, Takemoto S, Suzushima H, Kobayashi Y, Imaizumi Y, Yoshimura K, Kawamura K, Takahashi T, Tobinai K, and Ueda R
- Subjects
- Aged, Antibodies, Monoclonal, Humanized therapeutic use, Disease-Free Survival, Female, Humans, Male, Middle Aged, Survival Analysis, Treatment Outcome, Antibodies, Monoclonal, Humanized administration & dosage, Leukemia-Lymphoma, Adult T-Cell drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
The present study sought to elucidate the prognosis of adult T-cell leukemia-lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2017
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29. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002.
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Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, Tsukasaki K, Ito S, Yoshimitsu M, Otsuka M, Ogura M, Midorikawa S, Ruiz W, and Ohtsu T
- Subjects
- Administration, Oral, Aged, Aged, 80 and over, Angiogenesis Inhibitors administration & dosage, Disease Progression, Endpoint Determination, Female, Humans, Lenalidomide, Male, Middle Aged, Prognosis, Recurrence, Remission Induction, Survival Rate, Thalidomide administration & dosage, Thalidomide therapeutic use, Treatment Outcome, Angiogenesis Inhibitors therapeutic use, Leukemia-Lymphoma, Adult T-Cell drug therapy, Thalidomide analogs & derivatives
- Abstract
Purpose Few treatment options exist for adult T-cell leukemia/lymphoma (ATL), and the prognosis for this disease is poor. A phase I study of lenalidomide demonstrated preliminary antitumor activity in patients with relapsed ATL. The current phase II study evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed or recurrent ATL. Patients and Methods Patients 20 years of age or older with acute, lymphoma, or unfavorable chronic subtype ATL, who had received one or more prior anti-ATL systemic chemotherapy and achieved stable disease or better on their last anti-ATL therapy with subsequent relapse or recurrence, were eligible. Patients received oral lenalidomide 25 mg/d continuously until disease progression or unacceptable toxicity. The primary end point was overall response rate; secondary end points included safety, tumor control rate (stable disease or better), time to response, duration of response, time to progression, progression-free survival, and overall survival. Results Objective responses were noted in 11 of 26 patients (overall response rate, 42%; 95% CI, 23% to 63%), including four complete responses and one unconfirmed complete response. The tumor control rate was 73%. The median time to response and duration of response were 1.9 months and not estimable, respectively, and the median time to progression was 3.8 months. The median progression-free survival and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade ≥ 3 adverse events were neutropenia (65%), leukopenia (38%), lymphopenia (38%), and thrombocytopenia (23%), which were all manageable and reversible. Conclusion Lenalidomide demonstrated clinically meaningful antitumor activity and an acceptable toxicity profile in patients with relapsed or recurrent aggressive ATL, hinting at its potential to become a treatment option. Further investigations of lenalidomide in ATL and other mature T-cell neoplasms are warranted.
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- 2016
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30. Adult T-cell leukemia/lymphoma in donor cells responding to second allogeneic hematopoietic stem cell transplantation using unrelated cord blood: the Nagasaki Transplant Group experience.
- Author
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Itonaga H, Taguchi J, Taguchi M, Taniguchi H, Sato S, Sawayama Y, Imaizumi Y, Yoshida S, Hata T, Moriuchi Y, and Miyazaki Y
- Subjects
- Adult, Fetal Blood transplantation, Humans, Iatrogenic Disease, Leukemia-Lymphoma, Adult T-Cell blood, Male, Remission Induction, Transplantation, Homologous adverse effects, Unrelated Donors, Cord Blood Stem Cell Transplantation, Fetal Blood physiology, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia-Lymphoma, Adult T-Cell therapy, Tissue Donors
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- 2016
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31. PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma.
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Miyoshi H, Kiyasu J, Kato T, Yoshida N, Shimono J, Yokoyama S, Taniguchi H, Sasaki Y, Kurita D, Kawamoto K, Kato K, Imaizumi Y, Seto M, and Ohshima K
- Subjects
- Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Leukemia-Lymphoma, Adult T-Cell metabolism, Leukemia-Lymphoma, Adult T-Cell therapy, Male, Middle Aged, Neoplasm Staging, Prognosis, Retrospective Studies, Stromal Cells pathology, Survival Rate, B7-H1 Antigen metabolism, Biomarkers, Tumor metabolism, Leukemia-Lymphoma, Adult T-Cell pathology, Stromal Cells metabolism, Tumor Microenvironment
- Abstract
Programmed cell death ligand 1 (PD-L1) is expressed on both tumor and tumor-infiltrating nonmalignant cells in lymphoid malignancies. The programmed cell death 1 (PD-1)/PD-L1 pathway suppresses host antitumor responses, although little is known about the significance of PD-1/PD-L1 expression in the tumor microenvironment. To investigate the clinicopathological impact of PD-L1 expression in adult T-cell leukemia/lymphoma (ATLL), we performed PD-L1 immunostaining in 135 ATLL biopsy samples. We observed 2 main groups: 1 had clear PD-L1 expression in lymphoma cells (nPD-L1(+), 7.4% of patients), and the other showed minimal expression in lymphoma cells (nPD-L1(-), 92.6%). Within the nPD-L1(-) group, 2 subsets emerged: the first displayed abundant PD-L1 expression in nonmalignant stromal cells of the tumor microenvironment (miPD-L1(+), 58.5%) and the second group did not express PD-L1 in any cell (PD-L1(-), 34.1%). nPD-L1(+) ATLL (median survival time [MST] 7.5 months, 95% CI [0.4-22.3]) had inferior overall survival (OS) compared with nPD-L1(-) ATLL (MST 14.5 months, 95% CI [10.1-20.0]) (P = .0085). Among nPD-L1(-) ATLL, miPD-L1(+) ATLL (MST 18.6 months, 95% CI [11.0-38.5]) showed superior OS compared with PD-L1(-) ATLL (MST 10.2 months, 95% CI [8.0-14.7]) (P = .0029). The expression of nPD-L1 and miPD-L1 maintained prognostic value for OS in multivariate analysis (P = .0322 and P = .0014, respectively). This is the first report describing the clinicopathological features and outcomes of PD-L1 expression in ATLL. More detailed studies will disclose clinical and biological significance of PD-L1 expression in ATLL., (© 2016 by The American Society of Hematology.)
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- 2016
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32. Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia virus type-1 carriers.
- Author
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Kondo H, Soda M, Sawada N, Inoue M, Imaizumi Y, Miyazaki Y, Iwanaga M, Tanaka Y, Mizokami M, and Tsugane S
- Subjects
- Adult, Aged, Female, Humans, Japan, Male, Middle Aged, Risk Factors, Sex Factors, Human T-lymphotropic virus 1, Leukemia-Lymphoma, Adult T-Cell etiology, Smoking adverse effects
- Abstract
Background and Purpose: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive hematological malignancy caused by human T-cell leukemia virus type-1 (HTLV-1); no effective methods have yet been identified to prevent development of ATLL in carriers of HTLV-1. This study investigated the association between cigarette smoking and the risk of ATLL development among Japanese carriers of HTLV-1., Methods: This study examined the association between smoking and development of ATLL in a cohort of 1,332 Japanese HTLV-1 carriers aged 40-69 years free of ATLL at baseline from two different HTLV-1-endemic areas of Japan. Cox proportional hazards models adjusted for sex, geographic area, age at baseline, and alcohol drinking were used to estimate the effect of cigarette smoking on ATLL development., Results: Between 1993 and 2012, 25 new ATLL cases were identified among these subjects. The overall crude incidence rate for ATLL was 1.08 per 1,000 person-years among HTLV-1 carriers and was higher among male carriers than among female carriers (2.21 vs. 0.74). The risk of ATLL development increased significantly with increasing numbers of cigarettes smoked per day (hazard ratio for every increment of 20 cigarettes, 2.03; 95 % confidence interval (CI) 1.13-3.66 overall, 2.07 (95 % CI 1.13-3.73) in male carriers)., Conclusions: Cigarette smoking may influence ATLL development among HTLV-1 carriers in Japan.
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- 2016
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33. Induction of apoptosis by HBI-8000 in adult T-cell leukemia/lymphoma is associated with activation of Bim and NLRP3.
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Hasegawa H, Bissonnette RP, Gillings M, Sasaki D, Taniguchi H, Kitanosono H, Tsuruda K, Kosai K, Uno N, Morinaga Y, Imaizumi Y, Miyazaki Y, and Yanagihara K
- Subjects
- Acetylation drug effects, Annexin A5 metabolism, Antibodies, Caspase 3 metabolism, Cell Death drug effects, Cell Line, Tumor, Cell Survival drug effects, Histones drug effects, Histones metabolism, Humans, Inflammasomes metabolism, Membrane Potential, Mitochondrial, Oligonucleotide Array Sequence Analysis, Protein Array Analysis, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Apoptosis drug effects, Bcl-2-Like Protein 11 metabolism, Benzamides pharmacology, Leukemia-Lymphoma, Adult T-Cell metabolism, Leukemia-Lymphoma, Adult T-Cell pathology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Pyridines pharmacology
- Abstract
Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy caused by human T-cell lymphotropic virus 1. Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti-chemokine (C-C motif) receptor 4 antibody, although most patients still have a poor prognosis and there is a clear need for additional options. HBI-8000 is a novel oral histone deacetylase inhibitor with proven efficacy for treatment of T-cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI-8000 on ATL-derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI-8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested Bim activation and, interestingly, the contribution of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome pathway in HBI-8000-induced ATL cell death. Further investigations using siRNAs confirmed that Bim contributes to HBI-8000-induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI-8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI-8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2016
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34. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.
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Yoshida N, Miyoshi H, Kato T, Sakata-Yanagimoto M, Niino D, Taniguchi H, Moriuchi Y, Miyahara M, Kurita D, Sasaki Y, Shimono J, Kawamoto K, Utsunomiya A, Imaizumi Y, Seto M, and Ohshima K
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Leukemia-Lymphoma, Adult T-Cell metabolism, Leukemia-Lymphoma, Adult T-Cell mortality, Leukemia-Lymphoma, Adult T-Cell therapy, Male, Middle Aged, Phenotype, Prognosis, Receptors, CCR4 analysis, Time Factors, Biomarkers, Tumor genetics, Frameshift Mutation, Leukemia-Lymphoma, Adult T-Cell genetics, Receptors, CCR4 genetics
- Abstract
Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
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- 2016
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35. Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study.
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Ogura M, Imaizumi Y, Uike N, Asou N, Utsunomiya A, Uchida T, Aoki T, Tsukasaki K, Taguchi J, Choi I, Maruyama D, Nosaka K, Chen N, Midorikawa S, Ohtsu T, and Tobinai K
- Subjects
- Adult, Angiogenesis Inhibitors adverse effects, Humans, Lenalidomide, Leukemia-Lymphoma, Adult T-Cell pathology, Lymphoma, T-Cell, Peripheral pathology, Neutropenia chemically induced, Recurrence, Thalidomide administration & dosage, Thalidomide adverse effects, Thrombocytopenia chemically induced, Young Adult, Angiogenesis Inhibitors administration & dosage, Leukemia-Lymphoma, Adult T-Cell drug therapy, Lymphoma, T-Cell, Peripheral drug therapy, Thalidomide analogs & derivatives
- Abstract
Background: Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas., Methods: In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0-2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1-21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298., Findings: We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T-cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia [cohort 2], one grade 3 QT prolongation on electrocardiogram [cohort 3], and one grade 3 fatigue and grade 4 thrombocytopenia [cohort 3]). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight [62%] patients), lymphopenia (seven [54%] patients), and thrombocytopenia (four [31%] patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient., Interpretation: We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia-lymphoma. This dose will be used in a subsequent phase 2 study., Funding: Celgene Corporation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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36. Adult T-cell leukemia-lymphoma in a pregnant woman diagnosed as a human T-cell lymphotropic virus type 1 carrier.
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Fuchi N, Miura K, Imaizumi Y, Hasegawa H, Yanagihara K, Miyazaki Y, and Masuzaki H
- Subjects
- Adult, Female, Humans, Pregnancy, Human T-lymphotropic virus 1 pathogenicity, Leukemia-Lymphoma, Adult T-Cell, Pregnancy Complications, Infectious
- Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia-lymphoma (ATL), which is difficult to cure. In Japan, a nationwide HTLV-1 screening test in pregnant women has been recommended since 2011. A 30-year-old woman was diagnosed as being an HTLV-1 carrier in her previous pregnancy. During the current pregnancy, she had persistent fever and cough. Although she had treatment with antibiotics, peripheral white blood cell count remained high, with an abnormal lymphocyte count. Given that she was an HTLV-1 carrier, she was diagnosed with unfavorable chronic ATL (aggressive ATL) at 12 weeks gestation. After pregnancy termination, her ATL status became favorable chronic ATL (indolent ATL). Therefore, watchful waiting was performed until disease progression. This is the first case report of chronic ATL in early pregnancy, in a woman already diagnosed as an HTLV-1 carrier on screening test., (© 2015 Japan Society of Obstetrics and Gynecology.)
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- 2016
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37. Cord Blood Transplantation Provided Long-term Remission in a Case of Adult T-cell Leukemia-lymphoma (ATL) with Myelofibrosis.
- Author
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Itonaga H, Taguchi J, Kato T, Sato S, Sawayama Y, Imaizumi Y, Niino D, Hata T, Fukushima T, Ohshima K, and Miyazaki Y
- Subjects
- Humans, Male, Middle Aged, Remission Induction, Cord Blood Stem Cell Transplantation methods, Leukemia-Lymphoma, Adult T-Cell complications, Leukemia-Lymphoma, Adult T-Cell therapy, Myeloproliferative Disorders etiology
- Abstract
A 53-year-old man was diagnosed with adult T-cell leukemia-lymphoma (ATL) acute type transformed from chronic type. A bone marrow analysis showed diffuse infiltration of abnormal lymphocytes and diffuse fibrotic change. He received unrelated cord blood transplantation (CBT) following reduced-intensity conditioning with complete remission of ATL after two courses of chemotherapy and achieved neutrophil and platelet engraftment. At 99 days after CBT, a bone marrow biopsy showed apparent resolution of myelofibrosis. These results suggest the therapeutic potential of CBT for patients with chemosensitive ATL with myelofibrosis.
- Published
- 2016
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38. Integrated molecular analysis of adult T cell leukemia/lymphoma.
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Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, Totoki Y, Chiba K, Sato-Otsubo A, Nagae G, Ishii R, Muto S, Kotani S, Watatani Y, Takeda J, Sanada M, Tanaka H, Suzuki H, Sato Y, Shiozawa Y, Yoshizato T, Yoshida K, Makishima H, Iwanaga M, Ma G, Nosaka K, Hishizawa M, Itonaga H, Imaizumi Y, Munakata W, Ogasawara H, Sato T, Sasai K, Muramoto K, Penova M, Kawaguchi T, Nakamura H, Hama N, Shide K, Kubuki Y, Hidaka T, Kameda T, Nakamaki T, Ishiyama K, Miyawaki S, Yoon SS, Tobinai K, Miyazaki Y, Takaori-Kondo A, Matsuda F, Takeuchi K, Nureki O, Aburatani H, Watanabe T, Shibata T, Matsuoka M, Miyano S, Shimoda K, and Ogawa S
- Subjects
- Adult, Amino Acid Sequence, DNA Copy Number Variations, Gene Products, tax genetics, HEK293 Cells, Host-Pathogen Interactions genetics, Human T-lymphotropic virus 1 genetics, Human T-lymphotropic virus 1 physiology, Humans, Jurkat Cells, Leukemia-Lymphoma, Adult T-Cell virology, Molecular Sequence Data, Mutation, Sequence Homology, Amino Acid, Signal Transduction genetics, Survival Analysis, T-Lymphocytes metabolism, T-Lymphocytes virology, DNA Methylation, Exome genetics, Genome, Human genetics, Leukemia-Lymphoma, Adult T-Cell genetics, Sequence Analysis, DNA methods, Transcriptome genetics
- Abstract
Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.
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- 2015
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39. Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group.
- Author
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Itonaga H, Sawayama Y, Taguchi J, Honda S, Taniguchi H, Makiyama J, Matsuo E, Sato S, Ando K, Imanishi D, Imaizumi Y, Yoshida S, Hata T, Moriuchi Y, Fukushima T, and Miyazaki Y
- Subjects
- Adult, Aged, Aged, 80 and over, Allografts, Female, Humans, Japan, Lymphocytes pathology, Male, Middle Aged, Recurrence, Hematopoietic Stem Cell Transplantation, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell mortality, Leukemia-Lymphoma, Adult T-Cell pathology, Leukemia-Lymphoma, Adult T-Cell therapy
- Abstract
Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P<0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.
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- 2015
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40. Molecular analysis of loss of CCR4 expression during mogamulizumab monotherapy in an adult T cell leukemia/lymphoma patient.
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Taguchi M, Imaizumi Y, Sasaki D, Higuchi T, Tsuruda K, Hasegawa H, Taguchi J, Sawayama Y, Imanishi D, Hata T, Yanagihara K, Yoshie O, and Miyazaki Y
- Subjects
- Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents pharmacology, Flow Cytometry, Gene Expression Regulation, Leukemic, Humans, Leukemia-Lymphoma, Adult T-Cell genetics, Male, Middle Aged, Pathology, Molecular, Polymerase Chain Reaction, RNA Interference drug effects, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Leukemia-Lymphoma, Adult T-Cell drug therapy, Receptors, CCR4 genetics
- Published
- 2015
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41. Mutation Analysis for TP53 in Chronic-Type Adult T-Cell Leukemia/Lymphoma.
- Author
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Yoshida N, Imaizumi Y, Utsunomiya A, Miyoshi H, Arakawa F, Tsukasaki K, Ohshima K, and Seto M
- Subjects
- Cell Cycle genetics, Chronic Disease, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA Mutational Analysis, Disease Progression, Human T-lymphotropic virus 1, Humans, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell virology, Polymorphism, Single Nucleotide, Leukemia-Lymphoma, Adult T-Cell genetics, Mutation, Tumor Suppressor Protein p53 genetics
- Abstract
Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). ATLL is classified into four clinical subtypes based on the clinical manifestation: acute, lymphoma, chronic and smoldering. Approximately half of chronic type ATLL cases progressed to the acute type. We previously demonstrated that genomic alterations related to the cell cycle de-regulation such as CDKN2A and immune escape such as CD58 alteration can serve as predictive biomarkers for acute transformation of the chronic type. Although alteration of TP53, which is known to be a major regulator of cell cycle, has been identified in several types of cancers including acute type ATLL, no copy number alteration of TP53 was found in the chronic type by array comparative genomic hybridization. In the present study, mutation of TP53 was further analyzed by sequencing for these cases as well as HTLV-I carriers with oligo-clonality. However, no TP53 mutation was identified. These results suggested that TP53 mutation plays a role for the later stage of ATLL development.
- Published
- 2015
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42. Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells.
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Taniguchi H, Hasegawa H, Sasaki D, Ando K, Sawayama Y, Imanishi D, Taguchi J, Imaizumi Y, Hata T, Tsukasaki K, Uno N, Morinaga Y, Yanagihara K, and Miyazaki Y
- Subjects
- Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Survival drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Leukemia-Lymphoma, Adult T-Cell drug therapy, Antineoplastic Agents pharmacology, HSP90 Heat-Shock Proteins antagonists & inhibitors, Isoxazoles pharmacology, Leukemia-Lymphoma, Adult T-Cell pathology, Resorcinols pharmacology
- Abstract
Adult T-cell leukemia-lymphoma (ATL), an aggressive neoplasm etiologically associated with HTLV-1, is a chemoresistant malignancy. Heat shock protein 90 (HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. In this study, we examined NVP-AUY922 (AUY922), a second generation isoxazole-based non-geldanamycin HSP90 inhibitor, and confirmed its effects on survival of ATL-related cell lines. Analysis using FACS revealed that AUY922 induced cell-cycle arrest and apoptosis; it also inhibited the growth of primary ATL cells, but not of normal PBMCs. AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin. Interestingly, AUY922 induced downregulation of the proviral integration site for Moloney murine leukemia virus (PIM) in ATL cells. The PIM family (PIM-1, -2, -3) is made up of oncogenes that encode a serine/threonine protein kinase family. As PIM kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis, and tumorigenesis, their downregulation could play an important role in AUY922-induced death of ATL cells. In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines. Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)
- Published
- 2014
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43. Treatment outcome of elderly patients with aggressive adult T cell leukemia-lymphoma: Nagasaki University Hospital experience.
- Author
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Makiyama J, Imaizumi Y, Tsushima H, Taniguchi H, Moriwaki Y, Sawayama Y, Imanishi D, Taguchi J, Hata T, Tsukasaki K, and Miyazaki Y
- Subjects
- Age Factors, Aged, Aged, 80 and over, Cyclophosphamide, Disease Progression, Doxorubicin, Female, Humans, Induction Chemotherapy, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell mortality, Maintenance Chemotherapy, Male, Middle Aged, Neoplasm Staging, Prednisone, Retrospective Studies, Treatment Outcome, Vincristine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia-Lymphoma, Adult T-Cell drug therapy, Leukemia-Lymphoma, Adult T-Cell pathology
- Abstract
VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, and prednisone) is a standard regimen for aggressive adult T cell leukemia-lymphoma (ATL). However, the efficacy of this regimen has not been fully elucidated for patients aged 70 years or older. Here, we retrospectively analyzed elderly patients with aggressive ATL at Nagasaki University Hospital between 1994 and 2010 to assess treatment outcomes. Of 148 evaluable patients, 54 were aged 70 years or older at diagnosis. The median survival time (MST) and overall survival (OS) at 2 years in elderly patients were 10.6 months and 22.1%, respectively. Thirty-four patients received VCAP-AMP-VECP as the initial treatment, although the doses were reduced for most patients. In these patients, MST and OS at 2 years were 13.4 months and 26.6%, respectively. Eleven of 34 patients (32%) received maintenance oral chemotherapy after two or three cycles of VCAP-AMP-VECP, and MST and OS at 2 years were 16.7 months and 32.7%, respectively. Our results suggest that the VCAP-AMP-VECP regimen may be effective and that maintenance oral chemotherapy may be considered as a therapeutic option for elderly patients with aggressive ATL.
- Published
- 2014
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44. Molecular characterization of chronic-type adult T-cell leukemia/lymphoma.
- Author
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Yoshida N, Karube K, Utsunomiya A, Tsukasaki K, Imaizumi Y, Taira N, Uike N, Umino A, Arita K, Suguro M, Tsuzuki S, Kinoshita T, Ohshima K, and Seto M
- Subjects
- Adult, Aged, Aged, 80 and over, CD58 Antigens biosynthesis, Cyclin-Dependent Kinase Inhibitor p16 biosynthesis, Disease Progression, Female, Gene Expression Profiling, Humans, Leukemia-Lymphoma, Adult T-Cell pathology, Male, Middle Aged, Cell Cycle genetics, Gene Expression Regulation, Neoplastic genetics, Leukemia-Lymphoma, Adult T-Cell genetics, Neoplasm Proteins biosynthesis
- Abstract
Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1-induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, oligo-array comparative genomic hybridization and comprehensive gene expression profiling were applied to 27 and 35 cases of chronic and acute type ATL, respectively. The genomic profile of the chronic type was nearly identical to that of acute-type ATL, although more genomic alterations characteristic of acute-type ATL were observed. Among the genomic alterations frequently observed in acute-type ATL, the loss of CDKN2A, which is involved in cell-cycle deregulation, was especially characteristic of acute-type ATL compared with chronic-type ATL. Furthermore, we found that genomic alteration of CD58, which is implicated in escape from the immunosurveillance mechanism, is more frequently observed in acute-type ATL than in the chronic-type. Interestingly, the chronic-type cases with cell-cycle deregulation and disruption of immunosurveillance mechanism were associated with earlier progression to acute-type ATL. These findings suggested that cell-cycle deregulation and the immune escape mechanism play important roles in acute transformation of the chronic type and indicated that these alterations are good predictive markers for chronic-type ATL., (©2014 American Association for Cancer Research.)
- Published
- 2014
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45. Japan Clinical Oncology Group (JCOG) prognostic index and characterization of long-term survivors of aggressive adult T-cell leukaemia-lymphoma (JCOG0902A).
- Author
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Fukushima T, Nomura S, Shimoyama M, Shibata T, Imaizumi Y, Moriuchi Y, Tomoyose T, Uozumi K, Kobayashi Y, Fukushima N, Utsunomiya A, Tara M, Nosaka K, Hidaka M, Uike N, Yoshida S, Tamura K, Ishitsuka K, Kurosawa M, Nakata M, Fukuda H, Hotta T, Tobinai K, and Tsukasaki K
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Japan epidemiology, Leukemia-Lymphoma, Adult T-Cell pathology, Male, Middle Aged, Prognosis, Survivors, Young Adult, Leukemia-Lymphoma, Adult T-Cell mortality
- Abstract
This study evaluated the clinical features of 276 patients with aggressive adult T-cell leukaemia-lymphoma (ATL) in 3 Japan Clinical Oncology Group (JCOG) trials. We assessed the long-term survivors who survived >5 years and constructed a prognostic index (PI), named the JCOG-PI, based on covariates obtained by Cox regression analysis. The median survival time (MST) of the entire cohort was 11 months. In 37 patients who survived >5 years, no disease-related deaths in 10 patients with lymphoma-type were observed in contrast to the 10 ATL-related deaths in other types. In multivariate analysis of 193 patients, the JCOG-PI based on corrected calcium levels and performance status identified moderate and high risk groups with an MST of 14 and 8 months respectively (hazard ratio, 1·926). The JCOG-PI was reproducible in an external validation. Patients with lymphoma-type who survived >5 years might have been cured. The JCOG-PI is valuable for identifying patients with extremely poor prognosis and will be useful for the design of future trials combining new drugs or investigational treatment strategies., (© 2014 John Wiley & Sons Ltd.)
- Published
- 2014
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46. Meeting report on the possible proposal of an extranodal primary cutaneous variant in the lymphoma type of adult T-cell leukemia-lymphoma.
- Author
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Tsukasaki K, Imaizumi Y, Tokura Y, Ohshima K, Kawai K, Utsunomiya A, Amano M, Watanabe T, Nakamura S, Iwatsuki K, Kamihira S, Yamaguchi K, and Shimoyama M
- Subjects
- Humans, Leukemia-Lymphoma, Adult T-Cell pathology, Prognosis, Skin pathology, Skin Neoplasms pathology, Leukemia-Lymphoma, Adult T-Cell classification, Skin Neoplasms classification
- Abstract
Based on the advances in research on the clinicopathophysiology of adult T-cell leukemia-lymphoma (ATL), Japanese researchers collected and evaluated cases of smoldering ATL exhibiting primary cutaneous manifestation but showing poor prognosis. Macroscopic findings of skin eruptions were categorized into the patch, plaque, multipapular, nodulotumoral, erythrodermic and purpuric types, as previously reported. Pathological findings were divided into low or high grade based on epidermotropism, tumor cell size and perivascular infiltration. Eight eligible cases were evaluated among 14 collected cases. Macroscopic findings were nodulotumoral in six cases, a subcutaneous tumor in one case and plaque in one case, and the number and size were heterogeneous in each case. Pathological findings of all eight cases were T-cell lymphoma, high-grade type (pleomorphic, medium or large size), with prominent perivascular infiltration and scant epidermotropism. To diagnose such cases as the "lymphoma type of ATL, extranodal primary cutaneous variant", it is essential to examine each case carefully, including cutaneous lesions at onset, lymph nodes and other organ involvement using computed tomography (CT) and/or positron emission tomography/CT, as well as the percentage of abnormal lymphocytes in peripheral blood. Based on the results of an ongoing nationwide survey on ATL, ATL with cutaneous lesions will be analyzed to investigate the incidence and prognosis of the so-called "lymphoma type of ATL, extranodal primary cutaneous variant"., (© 2014 Japanese Dermatological Association.)
- Published
- 2014
- Full Text
- View/download PDF
47. [Outcome of patients with relapsed/refractory adult T-cell leukemia-lymphoma after salvage therapy].
- Author
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Taniguchi H, Imaizumi Y, Makiyama J, Itonaga H, Ando K, Sawayama Y, Imanishi D, Taguchi J, Tsushima H, Hata T, Hasegawa H, Hayashi T, Niino D, Ohshima K, Tsukasaki K, and Miyazaki Y
- Subjects
- Adult, Aged, Aged, 80 and over, Combined Modality Therapy methods, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Leukemia-Lymphoma, Adult T-Cell diagnosis, Leukemia-Lymphoma, Adult T-Cell mortality, Male, Middle Aged, Recurrence, Retrospective Studies, Treatment Outcome, Leukemia-Lymphoma, Adult T-Cell therapy, Salvage Therapy methods
- Abstract
We retrospectively analyzed 81 relapsed or refractory adult T-cell leukemia-lymphoma (ATL) patients who received salvage therapy in our institution between 2000 and 2010. These patients had received chemotherapy, radiation, or hematopoietic stem cell transplantation (HSCT) as an initial treatment, and were then given chemotherapy, radiation, HSCT, or donor lymphocyte infusion (DLI) as salvage therapy. Median survival time was 3.9 months. Of 5 long-term survivors, who survived more than 2 years after the first salvage therapy, 4 patients received HSCT or DLI, and the other was given mogamulizumab as the salvage therapy. For patients with relapsed or refractory ATL, HSCT/DLI is a promising treatment for achieving long-term survival. Mogamulizumab may be the good choice for those who are ineligible for HSCT.
- Published
- 2013
48. Transient proliferation of donor-derived ATL cell-like lymphocytes early after allogeneic stem cell transplantation in an adult T-cell leukemia/lymphoma patient.
- Author
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Taguchi M, Imaizumi Y, Taguchi J, Imanishi D, Sasaki D, Hasegawa H, Tsushima H, Hata T, and Miyazaki Y
- Subjects
- Humans, Leukemia-Lymphoma, Adult T-Cell immunology, Male, Middle Aged, Transplantation, Homologous, Cell Proliferation, Hematopoietic Stem Cell Transplantation, Leukemia-Lymphoma, Adult T-Cell pathology, Leukemia-Lymphoma, Adult T-Cell therapy, Lymphocytes pathology
- Published
- 2013
- Full Text
- View/download PDF
49. Distinct clinical features of infectious complications in adult T cell leukemia/lymphoma patients after allogeneic hematopoietic stem cell transplantation: a retrospective analysis in the Nagasaki transplant group.
- Author
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Itonaga H, Taguchi J, Fukushima T, Tsushima H, Sato S, Ando K, Sawayama Y, Matsuo E, Yamasaki R, Onimaru Y, Imanishi D, Imaizumi Y, Yoshida S, Hata T, Moriuchi Y, Honda S, and Miyazaki Y
- Subjects
- Adolescent, Adult, Aged, Antifungal Agents therapeutic use, Bacterial Infections complications, Bacterial Infections mortality, Bacterial Infections therapy, Cytomegalovirus Infections complications, Cytomegalovirus Infections mortality, Cytomegalovirus Infections therapy, Female, Fluconazole therapeutic use, Humans, Itraconazole therapeutic use, Japan, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Leukemia-Lymphoma, Adult T-Cell complications, Leukemia-Lymphoma, Adult T-Cell mortality, Leukemia-Lymphoma, Adult T-Cell therapy, Male, Middle Aged, Mycoses complications, Mycoses mortality, Mycoses therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Retrospective Studies, Survival Analysis, Transplantation, Homologous, Bacterial Infections pathology, Cytomegalovirus Infections pathology, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute pathology, Leukemia-Lymphoma, Adult T-Cell pathology, Mycoses pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Although allogeneic hematopoietic stem cell transplantation (allo-SCT) is performed as a curative option in adult T cell leukemia-lymphoma (ATL) patients, its high transplantation-related mortality raises a serious issue. The clinical features of infectious complications after transplantation are not well known. To analyze the impact of infections after allo-SCT for ATL, we retrospectively compared infectious complications in 210 patients at 3 institutions in Nagasaki prefecture between 1997 and 2009. There were 91 patients with acute myeloid leukemia (AML), 51 with acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL), and 68 with ATL. No patient received ganciclovir or foscarvir as prophylaxis, and most patients received antifungal prophylaxis with fluconazole or itraconazole. The cumulative incidence of cytomegalovirus (CMV) infection at 3 years was 69.2% in ATL patients versus 54.4% in AML patients (P = .0255). Cumulative infection-related mortality was significantly higher in ATL patients than in the 2 other groups (ATL versus AML, P = .0496; ATL versus ALL/LBL, P = .0075), and most death-causing pathogens were bacteria and fungus. The appearance of CMV infection was negatively associated with infectious mortality in ATL patients, but the P value for this association was near the borderline of significance (P = .0569). In multivariate analysis, transplantation using unrelated bone marrow and episodes of CMV infection were associated with worse overall survival in ATL patients, but were not in either AML or ALL/LBL patients. Collectively, the impact of infectious complications after transplantation in ATL patients was different from that in AML and ALL/LBL patients, suggesting that a more intensive strategy for infection control in ATL patients is required to reduce infectious mortality., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
50. Feasibility of cord blood transplantation in chemosensitive adult T-cell leukemia/lymphoma: a retrospective analysis of the Nagasaki Transplantation Network.
- Author
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Fukushima T, Itonaga H, Moriuchi Y, Yoshida S, Taguchi J, Imaizumi Y, Imanishi D, Tsushima H, Sawayama Y, Matsuo E, Hata T, and Miyazaki Y
- Subjects
- Adult, Cause of Death, Female, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Humans, Leukemia-Lymphoma, Adult T-Cell mortality, Male, Middle Aged, Retrospective Studies, Transplantation, Homologous, Treatment Outcome, Cord Blood Stem Cell Transplantation adverse effects, Leukemia-Lymphoma, Adult T-Cell therapy, Transplantation Conditioning
- Abstract
It has been reported that cord blood transplantation (CBT) for patients with aggressive adult T-cell leukemia/lymphoma (ATL) results in poorer outcomes than transplantation using other stem cell sources. To identify a subset of ATL in which CBT is feasible, we retrospectively analyzed 27 patients treated with CBT at three institutions in Nagasaki Prefecture, Japan. The estimated overall survival (OS) rate at 3 years was 27.4 %. Of 16 patients who received CBT during remission (complete, CR, or partial, PR), the OS rate at 3 years was 50 %, while during refractory periods (non-CR or non-PR), the OS rate was 9.1 %. Reduced intensity conditioning (RIC) was given to 18 patients, and myeloablative conditioning (MAC) was used in nine, with 3-year OS of 50.0 and 0 %, respectively. Of the 19 deaths, nine were due to progressive disease, eight (five MAC and three RIC) to infection, and two to multiple organ failure. These results suggest that CBT provides similar results with those in other transplantation procedures for selected ATL patients, such as those in CR or PR. Further studies are needed to evaluate the use of CBT in aggressive ATL.
- Published
- 2013
- Full Text
- View/download PDF
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