248 results on '"Kenji Ishitsuka"'
Search Results
2. Performance evaluation of Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test for different diagnostic situations
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Madoka Kuramitsu, Haruka Momose, Yuichiro Uchida, Kenji Ishitsuka, Ryuji Kubota, Masahito Tokunaga, Atae Utsunomiya, Kunihiko Umekita, Yuuki Hashikura, Kisato Nosaka, Ki-Ryang Koh, Hitomi Nakamura, Yasuko Sagara, Rieko Sobata, Masahiro Satake, Koh Nagata, Yuri Hasegawa, Daisuke Sasaki, Hiroo Hasegawa, Tomoo Sato, Yoshihisa Yamano, Kou Hiraga, Kenta Tezuka, Emi Ikebe, Sahoko Matsuoka, Kazu Okuma, Toshiki Watanabe, Kiyonori Miura, and Isao Hamaguchi
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immunochromatographic antibody test ,point-of-care test ,HTLV-1 ,sensitivity ,specificity ,Microbiology ,QR1-502 - Abstract
ABSTRACT Antibody screening tests for human T-cell leukemia virus type 1 (HTLV-1) are performed based on methods such as chemiluminescent enzyme immunoassay (CLEIA), chemiluminescence immunoassay (CLIA), electrochemiluminescence immunoassay, and particle agglutination (PA). Espline HTLV-I/II, a commercially available, easy-to-use, and rapid immunochromatographic antibody test (IC), was developed for situations where expensive instruments and laboratory equipment are not available. In this report, we compared the performance of IC with the above existing tests using diverse samples derived from asymptomatic HTLV-1 carriers and patients with HTLV-1-associated diseases in collaboration with 11 Japanese institutes. We found that IC detected HTLV-1 infection in all samples from HTLV-1-associated diseases, including adult T-cell leukemia, HTLV-1-associated myelopathy, and HTLV-1 uveitis (200/200). The sensitivity of IC compared with CLIA, CLEIA, and PA was 99.2% (363/366), 100% (241/241), and 100% (47/47), respectively, and the specificity was 99.4% (994/1000), 100% (60/60), and 100% (40/40), respectively. The positive and negative predictive values of IC were 99.7% [95% confidence interval (CI): 99.12–99.92] and 99.5% (95% CI: 98.82–99.75), respectively. However, IC had difficulty in correctly judging samples that were diagnosed as seroreactive in other first screening tests but negative by a confirmatory test; for example, of 612 confirmed negative samples that were CLIA seroreactive, 332 samples were IC positive. These results confirmed that IC has sufficient sensitivity and specificity as a screening test for HTLV-1, although, like the other screening tests, it also requires a confirmatory test to determine HTLV-1 infection correctly. IMPORTANCE The World Health Organization estimated that 5–10 million people are infected with human T-cell leukemia virus type 1 (HTLV-1). This number is likely to be underestimated because reliable endemic data are available for only approximately 1.5 billion people worldwide. The point-of-care test is a powerful tool for the easy and quick detection of infections without the requirement for expensive instruments and laboratory equipment. Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test that was evaluated in this study, might significantly advance our understanding of the global epidemiology of HTLV-1 infection.
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- 2023
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3. Gamma-secretase inhibitor does not induce cytotoxicity in adult T-cell leukemia cell lines despite NOTCH1 expression
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Shinsuke Suzuki, Sawako Hourai, Kimiharu Uozumi, Yuichirou Uchida, Makoto Yoshimitsu, Hachiman Miho, Naomichi Arima, Shin-ichi Ueno, and Kenji Ishitsuka
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NOTCH1 ,Adult T-cell leukemia/lymphoma ,γ-Secretase inhibitor ,Molecular pathogenesis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Activated mutations in NOTCH1 are drivers of T-cell type acute lymphoblastic leukemia/lymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemia/lymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Methods We analyzed the expression of NOTCH1 in six ATL- and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 (i.e., the cleaved form of NOTCH1) together with GSI on cell proliferation. Results Activated NOTCH1 found in ATL- and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of Tax expression (HTLV-1-coded protein). Whole-exome sequencing revealed that activated NOTCH1 mutations were undetectable in six ATL- and HTLV-1-infected cell lines, regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines. Conclusions These findings suggested that NOTCH1 protein is constitutively activated but is likely a passenger during NOTCH1-mutation-negative ATL cell proliferation.
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- 2022
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4. Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma
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Takuro Kameda, Keisuke Kataoka, Ayako Kamiunten, Michihiro Hidaka, Hiroaki Miyoshi, Nobuaki Nakano, Kisato Nosaka, Makoto Yoshimitsu, Jun-ichirou Yasunaga, Yasunori Kogure, Kotaro Shide, Masaharu Miyahara, Takashi Sakamoto, Keiichi Akizuki, Tomonori Hidaka, Yoko Kubuki, Junji Koya, Noriaki Kawano, Kiyoshi Yamashita, Hiroshi Kawano, Takanori Toyama, Kouichi Maeda, Kosuke Marutsuka, Yoshitaka Imaizumi, Koji Kato, Takeshi Sugio, Masahito Tokunaga, Yukie Tashiro, Akifumi Takaori-Kondo, Yasushi Miyazaki, Koichi Akashi, Kenji Ishitsuka, Masao Matsuoka, Koichi Ohshima, Toshiki Watanabe, Akira Kitanaka, Atae Utsunomiya, Seishi Ogawa, and Kazuya Shimoda
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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
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- 2023
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5. Landscape of immunoglobulin heavy chain γ gene class switch recombination in patients with adult T-cell leukemia–lymphoma
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Hiroaki Hiramatsu, Kisato Nosaka, Shigeru Kusumoto, Nobuaki Nakano, Ilseung Choi, Makoto Yoshimitsu, Yoshitaka Imaizumi, Michihiro Hidaka, Hidenori Sasaki, Junya Makiyama, Eiichi Ohtsuka, Tatsuro Jo, Masao Ogata, Asahi Ito, Kentaro Yonekura, Hiro Tatetsu, Takeharu Kato, Toshiro Kawakita, Youko Suehiro, Kenji Ishitsuka, Shinsuke Iida, Takaji Matsutani, Hiroyoshi Nishikawa, Atae Utsunomiya, Ryuzo Ueda, and Takashi Ishida
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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6. Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results
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Shinya Rai, Won Seog Kim, Kiyoshi Ando, Ilseung Choi, Koji Izutsu, Norifumi Tsukamoto, Masahiro Yokoyama, Kunihiro Tsukasaki, Junya Kuroda, Jun Ando, Michihiro Hidaka, Youngil Koh, Hirohiko Shibayama, Toshiki Uchida, Deok Hwan Yang, Kenji Ishitsuka, Kenichi Ishizawa, Jin Seok Kim, Hong Ghi Lee, Hironobu Minami, Hyeon Seok Eom, Mitsutoshi Kurosawa, Jae Hoon Lee, Jong Seok Lee, Won Sik Lee, Hirokazu Nagai, Takero Shindo, Dok Hyun Yoon, Shinichiro Yoshida, Mireille Gillings, Hiroshi Onogi, and Kensei Tobinai
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).
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- 2022
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7. Clinical and cytopathological characteristics of HTLV‐1+ hodgkin lymphoma
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Katsumi Kobata, Shoichi Kimura, Yasuhito Mihashi, Hiromi Iwasaki, Shuichi Nonaka, Shinji Matsumoto, Yasushi Takamatsu, Ilseung Choi, Shigeto Kawauchi, Kenji Ishitsuka, and Morishige Takeshita
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Human T‐lymphotropic virus‐1 (HTLV‐1)+ Hodgkin lymphoma (HL) is difficult to differentiate from adult T‐cell leukemia/lymphoma (ATLL) with HL‐like histology (HL‐like ATLL). Methods Cytological and immunohistological features, HTLV‐1 proviral DNA integration, and rearrangements of the T‐cell receptor (TCR) Cβ1 gene were examined in 11 HTLV‐1+ patients with HL‐like disease. Results Six patients were classified as HTLV‐1+ HL and five as HL‐like ATLL in accordance with genetic findings of HTLV‐1 proviral DNA integration and rearrangements of the TCR Cβ1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV‐1+ HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL‐like ATLL specimens, small‐ and medium‐sized atypical lymphocytes with indented and irregular‐shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30+ and CD15+ Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein‐Barr virus infection. The 50% overall survival period was significantly longer for the HTLV‐1+ HL group (180 months) than for the HL‐like ATLL group (7.8 months; P = .004). Conclusions HTLV‐1+ HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25+ and CCR4+ lymphocytes. In HTLV‐1 endemic areas, distinguishing HTLV‐1+ HL from HL‐like ATLL is important because of their differing treatment strategies and prognoses.
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- 2020
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8. Establishment of a novel diagnostic test algorithm for human T-cell leukemia virus type 1 infection with line immunoassay replacement of western blotting: a collaborative study for performance evaluation of diagnostic assays in Japan
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Kazu Okuma, Madoka Kuramitsu, Toshihiro Niwa, Tomokuni Taniguchi, Yumiko Masaki, Gohzoh Ueda, Chieko Matsumoto, Rieko Sobata, Yasuko Sagara, Hitomi Nakamura, Masahiro Satake, Kiyonori Miura, Naoki Fuchi, Hideaki Masuzaki, Akihiko Okayama, Kazumi Umeki, Yoshihisa Yamano, Tomoo Sato, Masako Iwanaga, Kaoru Uchimaru, Makoto Nakashima, Atae Utsunomiya, Ryuji Kubota, Kenji Ishitsuka, Hiroo Hasegawa, Daisuke Sasaki, Ki-Ryang Koh, Mai Taki, Kisato Nosaka, Masao Ogata, Isao Naruse, Noriaki Kaneko, Sara Okajima, Kenta Tezuka, Emi Ikebe, Sahoko Matsuoka, Kazuo Itabashi, Shigeru Saito, Toshiki Watanabe, and Isao Hamaguchi
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HTLV-1 infection ,HTLV-1 antibody ,Diagnostic algorithm ,Confirmatory test ,WB ,LIA ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background The reliable diagnosis of human T-cell leukemia virus type 1 (HTLV-1) infection is important, particularly as it can be vertically transmitted by breast feeding mothers to their infants. However, current diagnosis in Japan requires a confirmatory western blot (WB) test after screening/primary testing for HTLV-1 antibodies, but this test often gives indeterminate results. Thus, this collaborative study evaluated the reliability of diagnostic assays for HTLV-1 infection, including a WB-based one, along with line immunoassay (LIA) as an alternative to WB for confirmatory testing. Results Using peripheral blood samples from blood donors and pregnant women previously serologically screened and subjected to WB analysis, we analyzed the performances of 10 HTLV-1 antibody assay kits commercially available in Japan. No marked differences in the performances of eight of the screening kits were apparent. However, LIA determined most of the WB-indeterminate samples to be conclusively positive or negative (an 88.0% detection rate). When we also compared the sensitivity to HTLV-1 envelope gp21 with that of other antigens by LIA, the sensitivity to gp21 was the strongest. When we also compared the sensitivity to envelope gp46 by LIA with that of WB, LIA showed stronger sensitivity to gp46 than WB did. These findings indicate that LIA is an alternative confirmatory test to WB analysis without gp21. Therefore, we established a novel diagnostic test algorithm for HTLV-1 infection in Japan, including both the performance of a confirmatory test where LIA replaced WB on primary test-reactive samples and an additional decision based on a standardized nucleic acid detection step (polymerase chain reaction, PCR) on the confirmatory test-indeterminate samples. The final assessment of the clinical usefulness of this algorithm involved performing WB analysis, LIA, and/or PCR in parallel for confirmatory testing of known reactive samples serologically screened at clinical laboratories. Consequently, LIA followed by PCR (LIA/PCR), but neither WB/PCR nor PCR/LIA, was found to be the most reliable diagnostic algorithm. Conclusions Because the above results show that our novel algorithm is clinically useful, we propose that it is recommended for solving the aforementioned WB-associated reliability issues and for providing a more rapid and precise diagnosis of HTLV-1 infection.
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- 2020
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9. Effects of immune checkpoint inhibitor therapy resumption in patients with malignant tumors after moderate-to-severe immune-related adverse events.
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Machiko Kawahira, Shuji Kanmura, Keiko Mizuno, Kentaro Machida, Takao Ohtsuka, Masami Sato, Hideki Enokida, Masaru Yamashita, Takuro Kanekura, Shiho Arima, Norifumi Nakamura, Tsuyoshi Sugiura, Koji Yoshimoto, Hiroaki Kobayashi, Kenji Ishitsuka, Shinsuke Suzuki, Shinichi Ueno, and Akio Ido
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Medicine ,Science - Abstract
Background and aimsImmune checkpoint inhibitors (ICIs) are used to treat several cancers, but they sometimes induce immune-related adverse events (irAEs). Patients with irAEs often have improved antitumor responses, but discontinuation of ICIs after irAEs is considered necessary. Resuming the use of ICIs after irAEs is preferable, but few studies have investigated the safety of ICI resumption after irAEs. Therefore, we evaluated the factors associated with the recurrence of irAEs after ICI resumption to investigate the safety of this approach.MethodsIn this observational study, we enrolled patients treated with ICIs from September 2014 to March 2020 at our institution. Patient characteristics, ICIs, grades of irAEs, ICI discontinuation or resumption rates, and recurrence rates of irAEs after ICI therapy were analysed.ResultsTwo-hundred eighty-seven patients were included in the present study, and 76 patients experienced grade 2 or higher irAEs. Forty-two patients underwent ICI resumption after recovering from irAEs, and 13 of them had a recurrence of irAEs. Among those 13 patients, six had a recurrence of the same irAE, and seven experienced other irAEs. Ten of the 13 patients had grade ≥2 irAEs, and none had fatal irAEs. In the grade 2 or higher irAE group, more patients had irAEs associated with multiple organs and of initial grade ≥2 than those in the grade 1 and no recurrent irAEs group.ConclusionsPatients with initial multisystemic irAEs and irAEs of grade ≥2 were more likely to experience relapse or develop new grade ≥2 irAEs after ICI resumption.
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- 2022
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10. A survivin-responsive, conditionally replicating adenovirus induces potent cytocidal effects in adult T-cell leukemia/lymphoma
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Shinsuke Suzuki, Hiroki Kofune, Kimiharu Uozumi, Makoto Yoshimitsu, Naomichi Arima, Kenji Ishitsuka, Shin-ichi Ueno, and Ken-ichiro Kosai
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ATL ,Survivin ,Conditionally replicating adenoviruses ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Survivin-responsive, conditionally replicating adenoviruses regulated by multiple tumor-specific factors (Surv.m-CRAs), in which the expression of the adenoviral early region 1A gene is regulated by the survivin (BIRC5) promoter, can be used to treat several cancers. As survivin is overexpressed in ATL, we examined the effects of Surv.m-CRAs on ATL-selective replication and survival. Methods We tested two ATL cell lines and four HTLV-1-infected T-cell lines. The cells were subjected to infection with either E1-deleted, replication-defective adenoviruses or Surv.m-CRAs at various multiplicities of infection. Results Strong activation of survivin promoter was observed in all six cell lines. Moreover, the expression of the coxsackie and adenovirus receptor (CAR), which is important for adenoviral infection, was high in the cell lines. In contrast, we observed the absence of survivin promoter activity and a low expression of CAR in activated peripheral blood lymphocytes (PBLs) from healthy subjects. Surv.m-CRAs actively replicated and induced cytocidal effects in five out of six cell lines; conversely, we observed minimal viral replication and no marked cytotoxicity in normal activated PBLs. Conclusions This is the first report demonstrating that Surv.m-CRAs constitute attractive potential anti-ATL agents.
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- 2019
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11. Screening of Promising Chemotherapeutic Candidates from Plants against Human Adult T-Cell Leukemia/Lymphoma (VII): Active Principles from Thuja occidentalis L.
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Daisuke Nakano, Kenji Ishitsuka, Madoka Ishihara, Ryota Tsuchihashi, Masafumi Okawa, Kazuo Tamura, and Junei Kinjo
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screening ,adult T-cell leukemia/lymphoma ,Thuja occidentalis ,Organic chemistry ,QD241-441 - Abstract
During the screening of novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, we identified that the extracts of Thuja occidentalis (Cupressaceae) showed potent anti-proliferative activity in MT-1 and MT-2 cells. Therefore, we attempted to isolate the active components from this plant. We isolated and identified 32 compounds (1–32; eight lignans, 18 terpenoids, and six flavonoids) from the extracts of the leaves and cones. Their structures were determined by spectroscopic analysis. Several of the isolated compounds inhibited the growth of both cell lines. Lignans showed more potent activity than other classes of compounds. A comparison of the activities of compounds 1–8 revealed that the presence of a trans-lactone (linkage of C-6 to C-7) correlated with increased activity. Diterpenes showed moderate activity, and the presence of a ketone moiety at the C-7 position correlated with increased activity in compounds 12–21. In addition, biflavones showed moderate activity, and the presence of methoxy functions appeared to influence the activity of these compounds. Several lignans were lead compound of anti-cancer reagent (etoposide). In conclusion, not only lignans, but also diterpenes and/or biflavones, may be promising candidates for the treatment of adult T-cell leukemia/lymphoma.
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- 2021
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12. Therapeutic potential of arsenic trioxide with or without interferon-α for relapsed/refractory adult T-cell leukemia/lymphoma
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Kenji Ishitsuka, Junji Suzumiya, Mikiko Aoki, Kentaro Ogata, Shuuji Hara, and Kazuo Tamura
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Arsenic trioxide (As2O3) with or without interferon-α (IFN) was given to 4 patients with relapsed/refractory adult T-cell leukemia/lymphoma (ATLL). Treatment with As2O3 and IFN showed an encouraging response in two moderately-aggressive ATLL patients, while As2O3 alone was ineffective in two patients with very aggressive and rapidly progressing ATLL. Further studies are needed to clarify the role of As2O3 and its usefulness when combined with IFN for the treatment of ATLL.
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- 2007
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13. Genomic and phylogenetic characterization of Elizabethkingia anophelis strains: The first two cases of life-threatening infection in Japan
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Koji Ichiki, Tadasuke Ooka, Tetsuhiro Shinkawa, Sakura Inoue, Maiko Hayashida, Daisuke Nakamura, Masaki Akimoto, Makoto Yoshimitsu, Hideki Kawamura, Masatoshi Nakamura, Yuki Obama, Yasuhiro Gotoh, Tetsuya Hayashi, Junichiro Nishi, and Kenji Ishitsuka
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Microbiology (medical) ,Infectious Diseases ,Pharmacology (medical) - Published
- 2023
14. Identification of putative noncanonical driver mutations in patients with essential thrombocythemia
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Akihiko Arai, Makoto Yoshimitsu, Maki Otsuka, Yoshikiyo Ito, Takayoshi Miyazono, Nobuaki Nakano, Kosuke Obama, Hidetoshi Nakashima, Shuichi Hanada, Satsuki Owatari, Daisuke Nakamura, Masahito Tokunaga, Yuhei Kamada, Atae Utsunomiya, Koichi Haraguchi, Maiko Hayashida, Satoshi Fujino, Jun Odawara, Tomohisa Tabuchi, Shinsuke Suzuki, Heiichiro Hamada, Yoshiko Kawamoto, Yuichiro Uchida, Miho Hachiman, and Kenji Ishitsuka
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Hematology ,General Medicine - Published
- 2023
15. A decrease in newly diagnosed patients with adult T-cell leukemia/lymphoma in Kagoshima, a highly endemic area of HTLV-1 in southwestern Japan
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Satsuki Owatari, Masahito Tokunaga, Daisuke Nakamura, Kimiharu Uozumi, Yasuko Sagara, Hitomi Nakamura, Koichi Haraguchi, Nobuaki Nakano, Makoto Yoshimitsu, Yoshikiyo Ito, Atae Utsunomiya, Maki Otsuka, Shuichi Hanada, Masako Iwanaga, and Kenji Ishitsuka
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Cancer Research ,Oncology ,Hematology - Published
- 2023
16. Prognostic indices for peripheral T-cell lymphoma - not otherwise specified and adult T-cell leukemia/lymphoma: From past to future
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Kenji Ishitsuka
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General Medicine - Published
- 2023
17. Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (VIII): six new withanolides from Physalis philadelphica
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Daisuke Nakano, Kenji Ishitsuka, Yurie Deishi, Ryota Tsuchihashi, Junei Kinjo, Toshihiro Nohara, and Masafumi Okawa
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Molecular Medicine - Published
- 2023
18. Cord blood is a suitable donor source of allogeneic hematopoietic cell transplantation for adult T-cell leukemia-lymphoma: a nationwide retrospective study
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Masahito Tokunaga, Nobuaki Nakano, Shigeo Fuji, Atsushi Wake, Atae Utsunomiya, Ayumu Ito, Tetsuya Eto, Toshiro Kawakita, Yasuo Mori, Yukiyoshi Moriuchi, Youko Suehiro, Yasuhiko Miyazaki, Naoyuki Uchida, Yasushi Sawayama, Kenji Ishitsuka, Junya Kanda, Takafumi Kimura, Tatsuo Ichinohe, Yoshiko Atsuta, Takahiro Fukuda, Makoto Yoshimitsu, and Koji Kato
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Transplantation ,Hematology - Published
- 2023
19. The clinical benefit of acute GVHD depends on the age at transplantation in patients with adult T-cell leukemia–lymphoma on behalf of the ATL Working Group of the Japan Society for Transplantation and Cellular Therapy
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Shigeo Fuji, Yoshitaka Inoue, Junya Makiyama, Nobuaki Nakano, Ayumu Ito, Toshiro Kawakita, Tetsuya Eto, Youko Suehiro, Hidehiro Itonaga, Yasushi Sawayama, Yasuo Mori, Naoyuki Uchida, Satoko Morishima, Makoto Onizuka, Kenji Ishitsuka, Takahiro Fukuda, Yoshiko Atsuta, and Makoto Yoshimitsu
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Transplantation ,Hematology - Published
- 2023
20. 3. Malignant Lymphoma: an Update
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Kenji Ishitsuka
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General Medicine - Published
- 2022
21. Whole-genome landscape of adult T-cell leukemia/lymphoma
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Yoko Kubuki, Kengo Takeuchi, Seishi Ogawa, Yuki Tahira, Akifumi Takaori-Kondo, Kota Yoshifuji, Makoto Yoshimitsu, Kenichi Chiba, Masaaki Sekine, Ai Okada, Ana Acuna-Villaorduna, Yuichi Shiraishi, Yasushi Miyazaki, Tatsuhiro Shibata, Jun-ichirou Yasunaga, Tomonori Hidaka, Michihiro Hidaka, Mariko Tabata, Kisato Nosaka, Masao Matsuoka, Yasunori Kogure, Takuro Kameda, R. Alejandro Sica, Yuta Ito, B. Hilda Ye, Yoshitaka Imaizumi, Ayako Kamiunten, Sumito Shingaki, Keiichi Akizuki, Yuki Saito, Juan Carlos Ramos, Kazuya Shimoda, Junji Koya, Murali Janakiram, Marni B McClure, Urvi A Shah, Yasuhito Nannya, Kenji Ishitsuka, Mizuki Watanabe, Nobuaki Nakano, Satoru Miyano, Nobuyuki Kakiuchi, Atae Utsunomiya, Keisuke Kataoka, Kotaro Shide, and Akira Kitanaka
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DNA Copy Number Variations ,Immunology ,Somatic hypermutation ,Biology ,Biochemistry ,Genome ,Adult T-cell leukemia/lymphoma ,Mice ,Exome Sequencing ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,IL-2 receptor ,Gene ,Ataxin-1 ,Genetics ,Genome, Human ,Germinal center ,FOXP3 ,Cell Biology ,Hematology ,Prognosis ,medicine.disease ,Proto-Oncogene Proteins c-rel ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Repressor Proteins ,Survival Rate ,Leukemia ,Mutation ,Female - 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.
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- 2022
22. SRT1720 induces SIRT1‐independent cell death in adult T‐cell leukemia/lymphoma
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Tomohiro Kozako, Naho Kato, Takeo Ohsugi, Yu‐ichiro Uchida, Makoto Yoshimitsu, Kenji Ishitsuka, Yasuki Higaki, Haruna Sato, Akiyoshi Aikawa, and Shin‐ichiro Honda
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Mice ,Cell Death ,Sirtuin 1 ,Leukocytes, Mononuclear ,Animals ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Apoptosis ,Cell Biology ,Heterocyclic Compounds, 4 or More Rings ,Molecular Biology ,Biochemistry - Abstract
Adult T-cell leukemia/lymphoma (ATL) develops after a long period of human T-cell leukemia virus (HTLV)-1 infection and is associated with host aging in addition to genetic abnormalities in HTLV-1 infected cells. SIRT1 is a histone deacetylase involved in cell cycle and apoptosis. We previously showed the high expression of SIRT1 protein in peripheral blood mononuclear cells from patients with ATL. There have been many reports that SIRT1 inhibitors show tumor-suppressive effects. On the other hand, SIRT1 activator SRT1720 induces the cell death of multiple myeloma and breast cancer cells. However, the effect of SRT1720 on ATL is unknown. This study aimed to evaluate the effect of SRT1720 on cell death in leukemic cell lines in vitro and freshly isolated ATL cells ex vivo and in an ATL in vivo mouse model. SRT1720 reduced cell viability in vitro and ex vivo. Additionally, SRT1720 increased the number of apoptotic cells, as shown by annexin V positive cells, cleaved poly (ADP-ribose) polymerase 1, cleaved caspase-3, and fragmented DNA. SRT1720 also induced mitochondrial outer membrane permeabilization with the generation of mitochondrial reactive oxygen species and autophagy. However, SIRT1 knockdown did not attenuate SRT1720-induced cell death in leukemic cell lines. Finally, SRT1720 treatment decreased the growth of human ATL tumor xenografts in immunodeficient mice. Our study shows that while SRT1720 does not target SIRT1, it induces cell death in ATL cells via apoptosis and autophagy and has antitumor activity.
- Published
- 2022
23. 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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Takaji Matsutani, Eiichi Ohtsuka, Yoshitaka Imaizumi, Kenji Ishitsuka, Asahi Ito, Makoto Yoshimitsu, Kentaro Yonekura, Ilseung Choi, Atae Utsunomiya, Kisato Nosaka, Nobuaki Nakano, Shinsuke Iida, Ryuzo Ueda, Michihiro Hidaka, Toshiro Kawakita, Takashi Ishida, Youko Suehiro, Junya Makiyama, Hiro Tatetsu, Hidenori Sasaki, Shigeru Kusumoto, Takeharu Kato, Tatsuro Jo, and Masao Ogata
- Subjects
Adult ,Male ,Antibodies, Monoclonal, Humanized ,Peripheral blood mononuclear cell ,CD19 ,Immunoglobulin G ,Circulating Tumor DNA ,Antineoplastic Agents, Immunological ,Immune system ,Biomarkers, Tumor ,Mogamulizumab ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Clinical significance ,Receptor ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,biology ,business.industry ,Repertoire ,Genetic Variation ,Hematology ,Middle Aged ,Prognosis ,Survival Analysis ,Treatment Outcome ,Immunology ,Leukocytes, Mononuclear ,biology.protein ,Female ,Immunoglobulin Heavy Chains ,business ,medicine.drug - 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.
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- 2021
24. An Open-Label, Single-Arm, Phase 2 Trial of Valemetostat in Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma
- Author
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Koji Izutsu, Shinichi Makita, Kisato Nosaka, Makoto Yoshimitsu, Atae Utsunomiya, Shigeru Kusumoto, Satoko Morishima, Kunihiro Tsukasaki, Toyotaka Kawamata, Takaaki Ono, Shinya Rai, Hiroo Katsuya, Jun Ishikawa, Hironori Yamada, Kazunobu Kato, Masaya Tachibana, Yasuyuki Kakurai, Nobuaki Adachi, Kensei Tobinai, Kentaro Yonekura, and Kenji Ishitsuka
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR) (95% CI, 1.87 to NR; months). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. This trial was registered at www.clinicaltrials.gov as #NCT04102150.
- Published
- 2022
25. Clinical Features, Treatment Patterns, and Outcomes Among 837 Patients with Adult T-Cell Leukemia-Lymphoma in the Real-World Setting: A Comparison of Endemic Regions
- Author
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Bryan Valcarcel, Haruhiko Sano, Hiroo Katsuya, Atae Utsunomiya, Maki Otsuka, Masaharu Miyahara, Yasushi Takamatsu, Kenji Ishitsuka, Shinya Kimura, Junji Suzumiya, Kazuo Tamura, Daniel J Enriquez, Denisse Castro, Brady E Beltran, Henry Idrobo, Camila Peña, Lorena Fiad, Juan Carlos Ramos, and Luis Enrique Malpica Castillo
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
26. Validation of the Usefulness of Satl-PI and JCOG-PI As Predictors of Prognosis at the Start of Second-Line Treatment
- Author
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Daisuke Nakamura, Tomohisa Tabuchi, Naosuke Arima, Maiko Hayashida, Akihiko Arai, Makoto Yoshimitsu, and Kenji Ishitsuka
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
27. Progression of Disease within 5 Months of Adult T-Cell Leukemia-Lymphoma (ATL5) As a Clinical Endpoint for High-Risk Mortality Outcomes in the Real-World Setting: A Multinational Cohort Analysis
- Author
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Bryan Valcarcel, Haruhiko Sano, Hiroo Katsuya, Atae Utsunomiya, Maki Otsuka, Masaharu Miyahara, Yasushi Takamatsu, Kenji Ishitsuka, Shinya Kimura, Junji Suzumiya, Kazuo Tamura, Daniel J Enriquez, Denisse Castro, Brady E Beltran, Henry Idrobo, Camila Peña, Lorena Fiad, Juan Carlos Ramos, and Luis Enrique Malpica Castillo
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
28. 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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Yoshitaka Imaizumi, Masako Iwanaga, Kisato Nosaka, Kenji Ishitsuka, Kenichi Ishizawa, Shigeki Ito, Masahiro Amano, Takashi Ishida, Naokuni Uike, Atae Utsunomiya, Koichi Ohshima, Junji Tanaka, Yoshiki Tokura, Kensei Tobinai, Toshiki Watanabe, Kaoru Uchimaru, and Kunihiro Tsukasaki
- Subjects
Hematology - 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.
- Published
- 2022
29. Landscape of
- Author
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Hiroaki, Hiramatsu, Kisato, Nosaka, Shigeru, Kusumoto, Nobuaki, Nakano, Ilseung, Choi, Makoto, Yoshimitsu, Yoshitaka, Imaizumi, Michihiro, Hidaka, Hidenori, Sasaki, Junya, Makiyama, Eiichi, Ohtsuka, Tatsuro, Jo, Masao, Ogata, Asahi, Ito, Kentaro, Yonekura, Hiro, Tatetsu, Takeharu, Kato, Toshiro, Kawakita, Youko, Suehiro, Kenji, Ishitsuka, Shinsuke, Iida, Takaji, Matsutani, Hiroyoshi, Nishikawa, Atae, Utsunomiya, Ryuzo, Ueda, and Takashi, Ishida
- Abstract
Not available.
- Published
- 2022
30. Gamma-secretase inhibitor does not induce cytotoxicity in adult T cell leukemia cell lines despite NOTCH1 overexpression
- Author
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Shinsuke Suzuki, Sawako Hourai, Kimiharu Uozumi, Yuichirou Uchida, Makoto Yoshimitsu, Hachiman Miho, Naomichi Arima, Shin-ichi Ueno, and Kenji Ishitsuka
- Subjects
immune system diseases ,hemic and lymphatic diseases ,embryonic structures ,cardiovascular system ,biological phenomena, cell phenomena, and immunity - Abstract
Background: Activated mutations in Notch homolog 1, translocation-associated (Drosophila; NOTCH1) are driver oncogenes of T-cell type acute lymphoblastic leukemia/lymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemia/lymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Methods: We analyzed active NOTCH1 in six ATL and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 together with GSI on cell proliferation. Results: Activated NOTCH1 found in ATL and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of whether the contactin gene Tax, which encodes HTLV-1 protein, was expressed. Whole exome sequencing revealed that activated NOTCH1 mutations were undetectable in six cell lines infected with ATL and HTLV-1 regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines. Conclusions: These findings suggested that NOTCH1 protein is constitutively activated, but is likely a passenger during NOTCH1 mutation negative ATL cell proliferation.
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- 2022
31. Prediction of the risk for graft
- Author
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Yuhei, Kamada, Naosuke, Arima, Maiko, Hayashida, Daisuke, Nakamura, Makoto, Yoshimitsu, and Kenji, Ishitsuka
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Adult ,Cytomegalovirus Infections ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Antibodies, Monoclonal, Humanized ,Enteritis ,Retrospective Studies - Abstract
Mogamulizumab (Mog), an anti-C-C motif chemokine receptor 4 (CCR4) antibody, is a therapeutic for adult T-cell leukemia/lymphoma (ATL). Injuries of normal regulatory T cells (Tregs) which express CCR4 by Mog could result in immune-related adverse events including
- Published
- 2022
32. Prognosis of patients with adult T‐cell leukemia/lymphoma in Japan: A nationwide hospital‐based study
- Author
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Kunihiro Tsukasaki, Kisato Nosaka, Junji Tanaka, Kenji Ishitsuka, Kaoru Uchimaru, Yoshitaka Imaizumi, for collaborative Investigators, Masako Iwanaga, Masahiro Amano, Toshiki Watanabe, Kenichi Ishizawa, Koichi Ohshima, Naokuni Uike, Atae Utsunomiya, Yoshiki Tokura, Kensei Tobinai, Takashi Ishida, and Shigeki Ito
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,Vindesine ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,CHOP ,Nitrosourea Compounds ,0302 clinical medicine ,Japan ,immune system diseases ,Prednisone ,Cause of Death ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Leukemia-Lymphoma, Adult T-Cell ,Aged, 80 and over ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Middle Aged ,Prognosis ,Hospitals ,clinical subtypes ,Survival Rate ,Vincristine ,030220 oncology & carcinogenesis ,Original Article ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Cyclophosphamide ,Ranimustine ,Adult T-cell leukemia/lymphoma ,03 medical and health sciences ,Japanese nationwide survey ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,business.industry ,Epidemiology and Prevention ,Original Articles ,medicine.disease ,030104 developmental biology ,ATL ,Doxorubicin ,Health Care Surveys ,HTLV‐1 ,business - 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., The survival curve shows that the prognoses of patients with acute and lymphoma‐type ATL in Japan have improved modestly, but those of patients with chronic and smoldering‐type ATL have not improved.
- Published
- 2020
33. Establishment of a novel diagnostic test algorithm for human T-cell leukemia virus type 1 infection with line immunoassay replacement of western blotting: a collaborative study for performance evaluation of diagnostic assays in Japan
- Author
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Isao Hamaguchi, Masahiro Satake, Madoka Kuramitsu, Noriaki Kaneko, Kenta Tezuka, Sara Okajima, Atae Utsunomiya, Akihiko Okayama, Kisato Nosaka, Makoto Nakashima, Kazu Okuma, Masao Ogata, Mai Taki, Daisuke Sasaki, Naoki Fuchi, Gohzoh Ueda, Chieko Matsumoto, Yasuko Sagara, Kenji Ishitsuka, Toshiki Watanabe, Kiyonori Miura, Sahoko Matsuoka, Hideaki Masuzaki, Toshihiro Niwa, Shigeru Saito, Kazumi Umeki, Hitomi Nakamura, Tomokuni Taniguchi, Ryuji Kubota, Yoshihisa Yamano, Kazuo Itabashi, Isao Naruse, Rieko Sobata, Masako Iwanaga, Kaoru Uchimaru, Hiroo Hasegawa, Emi Ikebe, Yumiko Masaki, Ki-Ryang Koh, and Tomoo Sato
- Subjects
lcsh:Immunologic diseases. Allergy ,HTLV-1 infection ,Blotting, Western ,Diagnostic algorithm ,Antibodies, Viral ,Polymerase Chain Reaction ,Sensitivity and Specificity ,law.invention ,03 medical and health sciences ,WB ,Japan ,Proviruses ,Antigen ,Confirmatory test ,law ,Virology ,Humans ,Medicine ,Line immunoassay ,Polymerase chain reaction ,030304 developmental biology ,LIA ,Immunoassay ,Human T-lymphotropic virus 1 ,0303 health sciences ,biology ,Diagnostic Tests, Routine ,030306 microbiology ,business.industry ,Research ,Reproducibility of Results ,Diagnostic test ,HTLV-I Infections ,HTLV-1 Antibody ,Blot ,PCR ,Infectious Diseases ,HTLV-1 antibody ,biology.protein ,Reagent Kits, Diagnostic ,Antibody ,HTLV-I Antigens ,business ,lcsh:RC581-607 ,Algorithm ,Breast feeding ,Algorithms - Abstract
Background The reliable diagnosis of human T-cell leukemia virus type 1 (HTLV-1) infection is important, particularly as it can be vertically transmitted by breast feeding mothers to their infants. However, current diagnosis in Japan requires a confirmatory western blot (WB) test after screening/primary testing for HTLV-1 antibodies, but this test often gives indeterminate results. Thus, this collaborative study evaluated the reliability of diagnostic assays for HTLV-1 infection, including a WB-based one, along with line immunoassay (LIA) as an alternative to WB for confirmatory testing. Results Using peripheral blood samples from blood donors and pregnant women previously serologically screened and subjected to WB analysis, we analyzed the performances of 10 HTLV-1 antibody assay kits commercially available in Japan. No marked differences in the performances of eight of the screening kits were apparent. However, LIA determined most of the WB-indeterminate samples to be conclusively positive or negative (an 88.0% detection rate). When we also compared the sensitivity to HTLV-1 envelope gp21 with that of other antigens by LIA, the sensitivity to gp21 was the strongest. When we also compared the sensitivity to envelope gp46 by LIA with that of WB, LIA showed stronger sensitivity to gp46 than WB did. These findings indicate that LIA is an alternative confirmatory test to WB analysis without gp21. Therefore, we established a novel diagnostic test algorithm for HTLV-1 infection in Japan, including both the performance of a confirmatory test where LIA replaced WB on primary test-reactive samples and an additional decision based on a standardized nucleic acid detection step (polymerase chain reaction, PCR) on the confirmatory test-indeterminate samples. The final assessment of the clinical usefulness of this algorithm involved performing WB analysis, LIA, and/or PCR in parallel for confirmatory testing of known reactive samples serologically screened at clinical laboratories. Consequently, LIA followed by PCR (LIA/PCR), but neither WB/PCR nor PCR/LIA, was found to be the most reliable diagnostic algorithm. Conclusions Because the above results show that our novel algorithm is clinically useful, we propose that it is recommended for solving the aforementioned WB-associated reliability issues and for providing a more rapid and precise diagnosis of HTLV-1 infection.
- Published
- 2020
34. Effects of immune checkpoint inhibitor therapy resumption in patients with malignant tumors after moderate-to-severe immune-related adverse events
- Author
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Machiko Kawahira, Shuji Kanmura, Keiko Mizuno, Kentaro Machida, Takao Ohtsuka, Masami Sato, Hideki Enokida, Masaru Yamashita, Takuro Kanekura, Shiho Arima, Norifumi Nakamura, Tsuyoshi Sugiura, Koji Yoshimoto, Hiroaki Kobayashi, Kenji Ishitsuka, Shinsuke Suzuki, Shinichi Ueno, and Akio Ido
- Subjects
Multidisciplinary ,Immune System Diseases ,Humans ,Neoplasm Recurrence, Local ,Immune Checkpoint Inhibitors ,Lymphoma, Follicular - Abstract
Background and aims Immune checkpoint inhibitors (ICIs) are used to treat several cancers, but they sometimes induce immune-related adverse events (irAEs). Patients with irAEs often have improved antitumor responses, but discontinuation of ICIs after irAEs is considered necessary. Resuming the use of ICIs after irAEs is preferable, but few studies have investigated the safety of ICI resumption after irAEs. Therefore, we evaluated the factors associated with the recurrence of irAEs after ICI resumption to investigate the safety of this approach. Methods In this observational study, we enrolled patients treated with ICIs from September 2014 to March 2020 at our institution. Patient characteristics, ICIs, grades of irAEs, ICI discontinuation or resumption rates, and recurrence rates of irAEs after ICI therapy were analysed. Results Two-hundred eighty-seven patients were included in the present study, and 76 patients experienced grade 2 or higher irAEs. Forty-two patients underwent ICI resumption after recovering from irAEs, and 13 of them had a recurrence of irAEs. Among those 13 patients, six had a recurrence of the same irAE, and seven experienced other irAEs. Ten of the 13 patients had grade ≥2 irAEs, and none had fatal irAEs. In the grade 2 or higher irAE group, more patients had irAEs associated with multiple organs and of initial grade ≥2 than those in the grade 1 and no recurrent irAEs group. Conclusions Patients with initial multisystemic irAEs and irAEs of grade ≥2 were more likely to experience relapse or develop new grade ≥2 irAEs after ICI resumption.
- Published
- 2021
35. Author response for 'SRT1720 induces SIRT1‐independent cell death in adult T‐cell leukemia/lymphoma'
- Author
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null Tomohiro Kozako, null Naho Kato, null Takeo Ohsugi, null Yu‐ichiro Uchida, null Makoto Yoshimitsu, null Kenji Ishitsuka, null Yasuki Higaki, null Haruna Sato, null Akiyoshi Aikawa, and null Shin‐ichiro Honda
- Published
- 2021
36. Cardiac Involvement of Adult T Cell Leukemia/Lymphoma
- Author
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Kenji Ishitsuka, Nobuhito Ohno, Daisuke Ikeda, Katsunori Tofuku, Hidetoshi Nakashima, and Makoto Yoshimitsu
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Lymphoma ,viruses ,Autopsy ,Adult T-cell leukemia/lymphoma ,Left ventricular mass ,Refractory ,immune system diseases ,hemic and lymphatic diseases ,parasitic diseases ,Internal Medicine ,Medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Aged ,business.industry ,Systemic chemotherapy ,Myocardium ,hemic and immune systems ,General Medicine ,medicine.disease ,Leukemia ,business ,Cardiac symptoms - Abstract
Adult T-cell leukemia/lymphoma (ATL) is a refractory T-cell lymphoma with variable clinical profiles, commonly exhibiting extra-nodal involvement. The myocardial involvement of ATL is often detected at an autopsy; however, the development of a symptomatic cardiac mass due to ATL is extremely rare. We herein report a 65-year-old man with ATL who developed cardiac symptoms due to a rapidly enlarging left ventricular mass soon after the initiation of systemic chemotherapy. We also summarize previously reported cases of symptomatic ATL with cardiac involvement.
- Published
- 2021
37. [Development of future treatment for ATL]
- Author
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Kenji, Ishitsuka
- Subjects
Adult ,Human T-lymphotropic virus 1 ,Japan ,Humans ,Interferon-alpha ,Leukemia-Lymphoma, Adult T-Cell ,Molecular Targeted Therapy ,Aged - Abstract
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I. The clinical course of ATL is heterogeneous, and this condition has different types, which are as follows: acute, lymphoma, chronic, and smoldering. The chronic type is further subclassified into favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL and favorable chronic and smoldering-type ATL are defined as aggressive and indolent ATL, respectively. Newly identified prognostic indices based on clinical parameters and/or genetic predictors should be incorporated in the stratified treatment approach. The standard of care for aggressive ATL is multiagent chemotherapy, followed by allogeneic hematopoietic stem cell transplantation if applicable. Meanwhile, that for indolent ATL is watchful waiting until progression to the aggressive type. The combination of interferon-α and zidovudine is a treatment option for indolent ATL in other countries, and a confirmatory phase 3 trial is ongoing in Japan. In addition to mogamulizumab, lenalidomide, and brentuximab vedotin, which have been recently utilized in clinical practice, the use of a novel histone deacetylase (HDAC) inhibitor has been filed for approval. Moreover, an EZH1/2 inhibitor has completed the enrollment of a phase 2 trial in Japan. The standard of care for elderly patients should be established because the median age of those with newly diagnosed ATL reaches up to 70 years old.
- Published
- 2021
38. Epidemiology of adult T-cell leukemia-lymphoma in Japan: An updated analysis, 2012-2013
- Author
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Kenji Ishitsuka, Masako Iwanaga, Atae Utsunomiya, Yoshiki Tokura, Collaborative Investigators, Kisato Nosaka, Kunihiro Tsukasaki, Kaoru Uchimaru, Masahiro Amano, Toshiki Watanabe, Yoshitaka Imaizumi, and Shigeki Ito
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pediatrics ,Time Factors ,Databases, Factual ,Endemic Diseases ,viruses ,Malignancy ,registry data ,Adult T-cell leukemia/lymphoma ,nationwide survey ,Age Distribution ,Japan ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,Epidemiology ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Registries ,Sex Distribution ,Aged ,Retrospective Studies ,Aged, 80 and over ,Human T-lymphotropic virus 1 ,Hematology ,business.industry ,Cancer ,Epidemiology and Prevention ,General Medicine ,Original Articles ,Emigration and Immigration ,Middle Aged ,medicine.disease ,HTLV-I Infections ,Health Surveys ,Lymphoma ,adult T‐cell leukemia‐lymphoma ,Leukemia ,Oncology ,Female ,Original Article ,epidemiology ,Skin cancer ,HTLV‐1 ,business - 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., We identified that ATL patients shifted from areas endemic for HTLV‐1 to non‐endemic metropolitan areas. The median age at diagnosis was 69 y, which was significantly older than that in the 1980s and 1990s. We conducted a nationwide survey of ATL during 2012‐2013 by modifying data acquisition from 4 nationwide registries.
- Published
- 2021
39. A PHASE 2B OPEN‐LABEL SINGLE ARM STUDY TO EVALUATE THE EFFICACY AND SAFETY OF HBI‐8000 (TUCIDINOSTAT) IN PATIENTS WITH RELAPSED OR REFRACTORY PERIPHERAL T‐CELL LYMPHOMA (PTCL)
- Author
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Kunihiro Tsukasaki, M. Hidaka, Youngil Koh, Masahiro Yokoyama, W.S. Kim, Je-Hwan Lee, H. Onogi, Shinichiro Yoshida, Deok-Hwan Yang, Kenji Ishitsuka, Junya Kuroda, Dok Hyun Yoon, Koji Izutsu, Kiyoshi Ando, Kensei Tobinai, H. Nagai, Hirohiko Shibayama, Hong-ghi Lee, Shinya Rai, Takero Shindo, J. Ando, W. S. Lee, Kenichi Ishizawa, Ilseung Choi, M. Gillings, Hironobu Minami, Norifumi Tsukamoto, Mitsutoshi Kurosawa, H. S. Eom, Jin Soo Kim, and Toshiki Uchida
- Subjects
Oncology ,Refractory Peripheral T-cell Lymphoma ,Cancer Research ,medicine.medical_specialty ,business.industry ,Hematology ,General Medicine ,Tucidinostat ,Internal medicine ,medicine ,In patient ,Open label ,business ,Single Arm Study - Published
- 2021
40. FIRST‐IN‐HUMAN STUDY OF THE EZH1 AND EZH2 DUAL INHIBITOR VALEMETOSTAT TOSYLATE (DS‐3201B) IN PATIENTS WITH RELAPSED OR REFRACTORY NON‐HODGKIN LYMPHOMAS
- Author
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Eric D. Jacobsen, Toyotaka Kawamata, G Serbest, Kenji Ishitsuka, Kisato Nosaka, Shigeru Kusumoto, Nobuaki Adachi, Yoshitaka Imaizumi, Satoko Morishima, Kensei Tobinai, Kunihiro Tsukasaki, Dai Maruyama, Koji Izutsu, Kazunobu Kato, P Allen, Pierluigi Porcu, N. Yamauchi, Steve Horwitz, Shinichi Makita, Atae Utsunomiya, and Francine M. Foss
- Subjects
Cancer Research ,Oncology ,Refractory ,business.industry ,EZH2 ,Cancer research ,Dual inhibitor ,Medicine ,In patient ,Hematology ,General Medicine ,First in human ,business - Published
- 2021
41. Possibility of a risk‐adapted treatment strategy for untreated aggressive adult T‐cell leukaemia‐lymphoma ( <scp>ATL</scp> ) based on the <scp>ATL</scp> prognostic index: a supplementary analysis of the <scp>JCOG</scp> 9801
- Author
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Ryunosuke Machida, Hirokazu Nagai, Kosuke Toyoda, Kenji Ishitsuka, Dai Maruyama, Kunihiro Tsukasaki, Takuya Fukushima, and Tomohiro Kadota
- Subjects
Vincristine ,medicine.medical_specialty ,business.industry ,Hazard ratio ,Hematology ,Ranimustine ,Neutropenia ,medicine.disease ,Gastroenterology ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Prednisone ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Vindesine ,business ,Etoposide ,030215 immunology ,medicine.drug - Abstract
JCOG9801, a randomized phase III trial, reported that vincristine, cyclophosphamide, doxorubicin and prednisone (VCAP); doxorubicin, ranimustine and prednisone (AMP); and vindesine, etoposide, carboplatin and prednisone (VECP) (VCAP-AMP-VECP; mLSG15) showed superior clinical outcomes when compared to cyclophosphamide, doxorubicin, vincristine and prednisone every 2 weeks (CHOP-14; mLSG19) in patients with untreated aggressive adult T-cell leukaemia-lymphoma (ATL). To identify patients who require VCAP-AMP-VECP, we conducted a supplementary analysis of JCOG9801. Overall, 105 patients were included and categorized into low- (n = 44), intermediate- (n = 54) and high-risk (n = 7) groups according to the age-adjusted ATL prognostic index (ATL-PI). We excluded the high-risk group due to small numbers of patients. VCAP-AMP-VECP did not show any superior trend for overall survival (OS) in the low-risk group (hazard ratio: 1·04; 95% confidence interval: 0·54-2·04). Better OS was observed in the intermediate-risk group treated with VCAP-AMP-VECP (hazard ratio: 0·65; 95% confidence interval: 0·36-1·19). In the intermediate-risk group, the VCAP-AMP-VECP arm showed higher complete response rates than the CHOP-14 arm (44·0% vs. 13·8%). The VCAP-AMP-VECP arm in both risk groups exhibited grade 4 thrombocytopenia, while grade 4 neutropenia was only observed in the intermediate-risk group. VCAP-AMP-VECP remains suitable for the intermediate-risk group, whereas its benefits appear modest in the low-risk group.
- Published
- 2019
42. Safety and effectiveness of mogamulizumab in relapsed or refractory adult T‐cell leukemia‐lymphoma
- Author
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Kensei Tobinai, Takeshi Takahashi, Kenji Ishitsuka, Yukie Tsuji, Manabu Iwabuchi, and Satoshi Yurimoto
- Subjects
Male ,Oncology ,medicine.medical_specialty ,medicine.drug_class ,CCR4 ,Postmarketing surveillance ,Kaplan-Meier Estimate ,elderly patients ,Antibodies, Monoclonal, Humanized ,Monoclonal antibody ,03 medical and health sciences ,Chemokine receptor ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Refractory ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,Mogamulizumab ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,postmarketing surveillance ,In patient ,Prospective Studies ,Aged ,Aged, 80 and over ,relapsed or refractory ,business.industry ,mogamulizumab ,Original Articles ,Hematology ,General Medicine ,Middle Aged ,Refractory Adult T-Cell Leukemia/Lymphoma ,Treatment Outcome ,ATL ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Original Article ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Objective This prospective, observational, postmarketing surveillance was conducted to evaluate the safety and effectiveness of mogamulizumab, an anti‐CC chemokine receptor 4 (CCR4) monoclonal antibody, in patients with CCR4‐positive, relapsed or refractory (r/r) adult T‐cell leukemia‐lymphoma (ATL) in Japan. Method All patients were scheduled to receive intravenous infusions of mogamulizumab 1.0 mg/kg once weekly for 8 weeks, alone or in combination with other modalities. Results In the safety analysis population comprising 572 patients, mogamulizumab therapy was started between May 29, 2012, and April 30, 2013, and adverse drug reactions (ADRs) were reported in 73.4% (38.6% serious cases) of patients. The most common ADRs were skin disorders (33.2% [10.8% serious cases]), infusion‐related reactions (30.1% [4.7% serious cases]), and infections (22.0% [14.7% serious cases]). In the effectiveness analysis population comprising 523 patients, the best overall response rate and the response rate at the end of therapy were 57.9% and 42.0%, respectively. The median overall survival was 5.5 months. Safety and effectiveness results were similar between patients aged ≥70 and
- Published
- 2019
43. Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report
- Author
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Graham P. Taylor, Steve Horwitz, Takashi Ishida, Reza Farid, Horia Bumbea, Achiléa L. Bittencourt, Ali Bazarbachi, Lee Ratner, Akifumi Takaori-Kondo, Kaoru Uchimaru, Felipe Suarez, Shigeo Fuji, Toshiki Watanabe, Alina Tanase, Yoshitaka Imaizumi, Yoshiki Tokura, Takuya Fukushima, Thomas A. Waldmann, Adrienne A. Phillips, David Sibon, Olivier Hermine, Kenji Ishitsuka, Lucy Cook, Paul Fields, Ambroise Marçais, Kunihiro Tsukasaki, Atae Utsunomiya, Matthew A. Lunning, Ilseung Choi, Juan Carlos Ramos, Masao Matsuoka, Kate Cwynarski, and Imperial College Healthcare NHS Trust- BRC Funding
- Subjects
Oncology ,Cancer Research ,Skin Neoplasms ,Opportunistic infection ,COMBINATION CHEMOTHERAPY ,Disease ,Medical Oncology ,Central Nervous System Neoplasms ,0302 clinical medicine ,Risk Factors ,hemic and lymphatic diseases ,VERSUS-HOST-DISEASE ,Leukemia-Lymphoma, Adult T-Cell ,Medicine ,Human T-lymphotropic virus 1 ,0303 health sciences ,Hematopoietic Stem Cell Transplantation ,Combination chemotherapy ,3. Good health ,Treatment Outcome ,030220 oncology & carcinogenesis ,Life Sciences & Biomedicine ,NERVOUS-SYSTEM PROPHYLAXIS ,HTLV-1 PROVIRAL LOAD ,medicine.medical_specialty ,Consensus ,VIRUS TYPE-I ,Alpha interferon ,Antineoplastic Agents ,Malignancy ,Adult T-cell leukemia/lymphoma ,Special Article ,03 medical and health sciences ,Internal medicine ,LYMPHOTROPIC VIRUS ,Humans ,Transplantation, Homologous ,HEMATOPOIETIC STEM-CELLS ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,PROGNOSTIC INDEX ,030304 developmental biology ,Science & Technology ,business.industry ,CORD BLOOD TRANSPLANTATION ,medicine.disease ,Transplantation ,Clinical trial ,INTERFERON-ALPHA ,business - 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
- Published
- 2019
44. O3-1 HM-SCREEN-Japan 01: a mutation profiling multicenter study on patients with acute myeloid leukemia
- Author
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Naoko Hosono, Takahiro Yamauchi, Sunggi Chi, Seiichiro Katagiri, Akihiko Gotoh, Motoki Eguchi, Takanobu Morishita, Reiki Ogasawara, Takeshi Kondo, Masamitsu Yanada, Kazuhito Yamamoto, Tsutomu Kobayashi, Junya Kuroda, Kensuke Usuki, Yoshikazu Utsu, Nobuyuki Aotsuka, Makoto Yoshimitsu, Kenji Ishitsuka, Takaaki Ono, and Yosuke Minami
- Subjects
Oncology ,Hematology - Published
- 2022
45. MO10-2 Emerging molecular targets in AML: IDH1/2- and menin-related mutations (HM-SCREEN-JAPAN01)
- Author
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Sunggi Chi, Satoshi Uchiyama, Makoto Yoshimitsu, Kenji Ishitsuka, Kaoru Yamamoto, Yukinori Nakamura, Takahashi Naoto, Takeshi Kondo, Kensuke Usuki, Takaaki Ono, Tsutomu Kobayashi, Junya Kuroda, Satoshi Iyama, Makoto Nakamura, Kensuke Kojima, Suguru Fukuhara, Koji Izutsu, Nobuhiko Yamauchi, Junichiro Yuda, and Yosuke Minami
- Subjects
Oncology ,Hematology - Published
- 2022
46. A retrospective analysis of haplo-identical HLA-mismatch hematopoietic transplantation without posttransplantation cyclophosphamide for GVHD prophylaxis in patients with adult T-cell leukemia–lymphoma
- Author
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Shigeo Fuji, Kazuyoshi Ishii, Kaname Miyashita, Atae Utsunomiya, Takahiro Fukuda, Makoto Yoshimitsu, Tetsuya Eto, Hiroshi Fujiwara, Hirokazu Okumura, Hiroyasu Ogawa, Junji Tanaka, Yoshifusa Takatsuka, Yoshiko Atsuta, Kenji Ishitsuka, Akira Yokota, Akihito Yonezawa, Koji Kato, Junichi Tsukada, and Akinori Nishikawa
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Adult T-cell leukemia/lymphoma ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Retrospective Studies ,Transplantation ,business.industry ,Histocompatibility Testing ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,medicine.disease ,HLA Mismatch ,Clinical trial ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Cord blood ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Currently, allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative modality for patients with adult T-cell leukemia-lymphoma (ATL). When used in conjunction with posttransplantation cyclophosphamide (PTCY) for graft-versus-host disease prophylaxis, allo-HCT from an HLA haplo-identical donor yields promising outcomes for many diseases other than ATL. However, appropriate comparisons with other donor sources, especially cord blood and conventional HLA haplo-identical donors, are needed to validate the safety and efficacy of this modality. In this study, we retrospectively evaluated the outcome of allo-HCT without PTCY in patients with ATL registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database between 1985 and 2015. During that period, 46 patients received allo-HCT without PTCY and survivors were followed for a median of 2316.5 days (range: 220-3884 days). Although the estimated 1- and 5-year overall survival rates of the entire cohort were 34.5% and 17.7%, respectively, the cumulative 1- and 5-year non-ATL mortality rates of 41.3% and 55.8%, respectively, were high. The results of our study will serve as a platform for discussions of the safety and efficacy of haplo-HCT for future clinical trials in patients with ATL.
- Published
- 2018
47. Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial
- Author
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Masashi Wakabayashi, Takahiko Utsumi, Yasuo Morishima, Yoshifusa Takatsuka, Kazutaka Sunami, Hiroshi Gomyo, Shinya Rai, Kenji Ishitsuka, Takaki Shimada, Hideki Tsujimura, Sawako Nakachi, Naoki Kobayashi, Isao Yoshida, Takashi Terauchi, Takashi Watanabe, Naoto Takahashi, Yurie Saitoh, Hidenori Sasaki, Kazuma Ohyashiki, Takashi Tokunaga, Yoshihiro Yakushijin, Tsutomu Kobayashi, Jo Kanasugi, Tomohiro Kinoshita, Takaaki Chou, Kazuyuki Shimada, Kisato Nosaka, Yukiyoshi Moriuchi, Masako Yokoo, Makoto Yoshimitsu, Yoshihiro Kameoka, Hiroaki Asai, Shinsuke Iida, Shigeru Kusumoto, Akihiko Yokohama, Kensei Tobinai, Koichiro Minauchi, Tadashi Yoshino, Junichi Tsukada, Hirokazu Nagai, Tatsuro Jo, Naokuni Uike, Yoshitaka Imaizumi, Nobuhiko Yamauchi, Tatsu Shimoyama, Eiichi Ohtsuka, Hirofumi Kobayashi, Takahiro Yamauchi, Yoshitoyo Kagami, Harumi Kato, Shinya Kimura, Yasushi Takamatsu, Tomomitsu Hotta, Junya Kuroda, Yoko Ushijima, Michinori Ogura, Nobuyuki Takayama, Naoko Harada, Kunihiro Tsukasaki, Youko Suehiro, Masafumi Taniwaki, Tohru Murayama, Satoshi Yamasaki, Masanori Makita, Yosuke Minami, Fumiaki Sano, Yasushi Miyazaki, Kyoya Kumagai, Shin Matsuda, Kazuhito Yamamoto, Yutaro Kamiyama, Kayo Yamagishi, Noriko Fukuhara, Toshiki Uchida, Izumi Wasada, Takuro Ishiguro, Daigo Akahane, Nobuaki Dobashi, Ichiro Hanamura, Noriyasu Fukushima, Sigeru Nawano, Michihiro Hidaka, Koji Izutsu, Hiro Tatetsu, Kiyoshi Ando, Shinichiro Yoshida, Itaru Matsumura, Tatsuo Ichinohe, Madoka Takimoto, Kana Miyazaki, Junji Hiraga, Yasufumi Masaki, Ilseung Choi, Hiroaki Morimoto, Norifumi Tsukamoto, Atae Utsunomiya, Mitsutoshi Kurosawa, Dai Maruyama, Takaaki Ono, Takayo Suzuki, Motoko Yamaguchi, Satoko Morishima, Hideo Harigae, and Nobuko Kubota
- Subjects
Male ,medicine.medical_specialty ,Follicular lymphoma ,Antibodies, Monoclonal, Murine-Derived ,03 medical and health sciences ,0302 clinical medicine ,Prednisone ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,Humans ,Cumulative incidence ,Cyclophosphamide ,Lymphoma, Follicular ,business.industry ,Standard treatment ,Hazard ratio ,Hematology ,Middle Aged ,medicine.disease ,Clinical trial ,Treatment Outcome ,Doxorubicin ,Vincristine ,030220 oncology & carcinogenesis ,Female ,Rituximab ,business ,Follow-Up Studies ,030215 immunology ,medicine.drug - Abstract
Summary Background Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3–7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25–41; R-CHOP-14 39%, 31–47; hazard ratio 0·89, 95% CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39% (33–45) at 8 years and 36% (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5–6·0) at 5 years, 8·5% (5·4–12·4) at 8 years, and 9·3% (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3–5·5). Interpretation R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding National Cancer Center and Ministry of Health, Labour and Welfare of Japan.
- Published
- 2018
48. Long-term follow-up of patients with ATL after autologous stem cell transplantation
- Author
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Atae Utsunomiya, Masahito Tokunaga, Nobuaki Nakano, Hiroshi Fujiwara, Toshihiro Miyamoto, Masao Ogata, Yasuhiko Miyazaki, Kenji Ishitsuka, Emiko Sakaida, Hirofumi Taji, Toshio Wakayama, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Koji Kato, and Makoto Yoshimitsu
- Subjects
Transplantation ,Hematopoietic Stem Cell Transplantation ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Transplantation, Homologous ,Hematology ,Transplantation, Autologous ,Follow-Up Studies ,Stem Cell Transplantation - Published
- 2021
49. Diagnosis and management of adult T-cell leukemia/lymphoma
- Author
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Kenji Ishitsuka
- Subjects
Oncology ,Adult ,medicine.medical_specialty ,viruses ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Adult T-cell leukemia/lymphoma ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,parasitic diseases ,medicine ,Mogamulizumab ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Brentuximab vedotin ,Lenalidomide ,Human T-lymphotropic virus 1 ,business.industry ,Hematopoietic Stem Cell Transplantation ,Interferon-alpha ,hemic and immune systems ,Hematology ,medicine.disease ,Prognosis ,Lymphoma ,Leukemia ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug - Abstract
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1). Between 3% and 5% of HTLV-1-infected individuals develop ATL after a long latency. Confirmation of seropositivity of anti-HTLV-1 antibody, and clonal proliferation of CD4 and CD25 positive lymphocytes with nuclear pleomorphism in patients suspicious of malignant lymphoma or chronic lymphocytic leukemia is crucial for the diagnosis of ATL. The clinical course of ATL is very heterogeneous, and divided into acute, lymphoma, chronic, and smoldering types. The chronic type is further subclassified into the favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL, and favorable chronic and smoldering type ATL are defined as aggressive and indolent ATL, respectively. Recently identified prognostic indices based on clinical parameters and/or genetic predictors of outcomes need to be confirmed and incorporated for more stratified therapeutic interventions. The standard of care for aggressive ATL is multiagent chemotherapy followed by allogeneic hematopoietic stem cell transplantation if possible, while that for indolent ATL is watchful waiting until progression to aggressive ATL. The combination of interferon-α and zidovudine is also standard for leukemic type ATL. In addition, mogamulizumab, lenalidomide, and brentuximab vedotin have been incorporated into clinical practices in Japan. Furthermore, several novel drugs are currently undergoing clinical trials.
- Published
- 2020
50. Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study
- Author
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Yukiyoshi Moriuchi, Kisato Nosaka, Asahi Ito, Yasushi Miyazaki, Nobuaki Nakano, Ilseung Choi, Takashi Ishida, Kentaro Yonekura, Michihiro Hidaka, Tatsuro Jo, Masao Ogata, Makoto Yoshimitsu, Shigeru Kusumoto, Yoshitaka Imaizumi, Kenji Ishitsuka, Atae Utsunomiya, Eiichi Ohtsuka, Hiro Tatetsu, Youko Suehiro, Ryuzo Ueda, and Hidenori Sasaki
- Subjects
Oncology ,Adult ,medicine.medical_specialty ,Immunobiology and Immunotherapy ,Lymphocyte ,Population ,Antibodies, Monoclonal, Humanized ,Adult T-cell leukemia/lymphoma ,Immune system ,Internal medicine ,hemic and lymphatic diseases ,Mogamulizumab ,Medicine ,Cytotoxic T cell ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,education ,education.field_of_study ,business.industry ,Hematology ,medicine.disease ,Lymphoma ,medicine.anatomical_structure ,Leukocytes, Mononuclear ,business ,CD8 ,medicine.drug ,T-Lymphocytes, Cytotoxic - 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.
- Published
- 2020
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