176 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. 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
14. 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
15. 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.
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- 2022
16. Clinical significance of the immunoglobulin G heavy‐chain repertoire in peripheral blood mononuclear cells of adult T‐cell leukaemia–lymphoma patients receiving mogamulizumab
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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
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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.
- Published
- 2021
17. An Open-Label, Single-Arm, Phase 2 Trial of Valemetostat in Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma
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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
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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
18. 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
19. 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
20. 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
21. 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
22. 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.
- Published
- 2022
23. 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
24. 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
25. 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
26. 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
27. 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
28. 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
29. 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
30. 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
31. 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
32. 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
33. 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
34. 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
35. 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
36. 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
37. Screening of Promising Chemotherapeutic Candidates from Plants against Human Adult T-Cell Leukemia/Lymphoma (VI): Cardenolides from Asclepias curassavica
- Author
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Kenji Ishitsuka, Daisuke Nakano, Junei Kinjo, Aya Satou, Ryota Tsuchihashi, Maya Takashima, Kazuo Tamura, Rie Arima, and Masafumi Okawa
- Subjects
0301 basic medicine ,Asclepias curassavica ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Pharmacology ,Peripheral blood mononuclear cell ,Adult T-cell leukemia/lymphoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Cardenolide ,Cytotoxic T cell ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Asclepias ,biology ,Dose-Response Relationship, Drug ,Chemistry ,Plant Extracts ,General Medicine ,Cell cycle ,medicine.disease ,biology.organism_classification ,Antineoplastic Agents, Phytogenic ,Leukemia ,Cardenolides ,030104 developmental biology ,030220 oncology & carcinogenesis ,Growth inhibition - Abstract
In the course of our screening program for novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, the extracts of Asclepias curassavica L. showed potent activity against MT-1 and MT-2 cells. Therefore, we attempted to isolate their active components. We identified a new cardenolide, 19-dihydrocalactinic acid methyl ester (1), along with 16 known cardenolides (2-17). Their structures were determined on the basis of spectroscopic data. Almost all of the isolated cardenolides inhibited the growth of both tumor cell lines. All the doubly linked cardenolides (11-17) except for 14 showed more potent activity than the other cardenolides. A comparison of the activities of 11, 14 and 16 revealed that the presence of hydroxy or acetoxy functional groups at C-16 led to a decrease in the activity. The 50% effective concentration (EC50) value of calotropin (11) against MT-2 cells was comparable to the potency of the clinical antineoplastic drug doxorubicin. The cytotoxic effect of 11 toward normal mononuclear cells obtained from the peripheral blood (PB-MNCs) was observed at a concentration 6 to 12 times higher than that used to induce growth inhibition against MT-1 and MT-2 cells. The proportions of annexin V-positive cells after 72 h of treatment with 11 were increased, indicating that it significantly induced apoptosis in MT-1 and MT-2 cells in a concentration-dependent manner. Cell cycle experiments demonstrated that 11 arrested MT-1 and MT-2 cells at the G2/M phase. Therefore, compound 11 may be a promising candidate for the treatment of adult T-cell leukemia/lymphoma.
- Published
- 2020
38. Novel Anti-CD70 Antibody Drug Conjugate for the Treatment of Adult T-Cell Leukemia (ATL)
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Masaaki Toyama, Makoto Yoshimitsu, Kenji Ishitsuka, Ikuko Watanabe, Satoshi Kishimoto, Riri Yokota, Yuji Ito, Shun Hashimoto, Masanori Baba, and Mika Okamoto
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Adult ,Male ,Cancer Research ,Antibody-drug conjugate ,Immunoconjugates ,Cell Survival ,medicine.medical_treatment ,T-cell leukemia ,Jurkat Cells ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Maytansine ,CD70 ,Cell Proliferation ,Chemotherapy ,biology ,Cell growth ,business.industry ,General Medicine ,Immunotherapy ,Middle Aged ,medicine.disease ,Leukemia ,Oncology ,Cancer research ,biology.protein ,Female ,Antibody ,business ,CD27 Ligand ,Single-Chain Antibodies - Abstract
Background/aim Adult T-cell leukemia (ATL) is a hematological malignancy caused by infection with human T-cell leukemia virus type 1 (HTLV-1). Chemotherapy, antibody therapy, and bone marrow transplantation are used to treat this disease, however, median survival time has not been significantly improved. Our aim was to develop and evaluate a novel antibody-drug conjugate (ADC) with regards to cell cytotoxicity and target specificity. Materials and methods In this study, we have constructed a novel ADC, which is composed of an anti-CD70 single chain Fv-Fc antibody conjugated with the anticancer agent emtansine using a novel antibody modification method. Cell cytotoxicity and target specificity were assessed using a cell proliferation assay. Results The anti-CD70 ADC selectively killed HTLV-1-infected cells and ATL cells without affecting other cells. Conclusion The anti-CD70 ADC offers some chemotherapeutic potential for the treatment of ATL.
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- 2020
39. The small molecule STF-62247 induces apoptotic and autophagic cell death in leukemic cells
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Hidetoshi Kamimura, Keisuke Sato, Makoto Yoshimitsu, Yasuki Higaki, Hiroaki Tanaka, Shin-ichiro Honda, Haruna Uemura, Kenji Ishitsuka, Akiyoshi Aikawa, Kentaro Ogata, Naho Kato, Yuichiro Uchida, Shinji Soeda, and Tomohiro Kozako
- Subjects
0301 basic medicine ,autophagy ,Programmed cell death ,Chemistry ,T cell ,T-cell leukemia ,Cell ,Autophagy ,apoptosis ,Jurkat cells ,Human T cell leukemia virus-1 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Apoptosis ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,adult T cell leukemia/lymphoma ,Viability assay ,STF-62247 ,Research Paper - Abstract
Adult T cell leukemia/lymphoma (ATL) is an aggressive malignant T cell disease caused by human T cell leukemia virus-I (HTLV-1). Treatment outcomes for aggressive subtypes of ATL remain poor, with little improvement in overall survival since HTLV-1 was discovered. Therefore, new therapeutic strategies for ATL are required. STF-62247 induces autophagy and selectively kills renal cell carcinoma without apoptotic cell death. Here, we demonstrate that STF-62247 reduced cell viability and resulted in autophagosome accumulation and autophagy in leukemic cell lines (S1T, MT-2, and Jurkat). Interestingly, STF-62247 induced apoptosis in HTLV-1-infected cell lines (S1T and MT-2), as indicated by DNA fragmentation and caspase activation, but not in non-HTLV-1-infected Jurkat cells; a caspase inhibitor did not prevent this caspase-associated cell death. STF-62247 also increased nuclear endonuclease G levels. Furthermore, STF-62247 reduced cell viability and increased the number of apoptotic cells in peripheral blood mononuclear cells collected from patients with acute ATL, which has a poor prognosis. Therefore, STF-62247 may have novel therapeutic potential for ATL. This is the first evidence to demonstrate the cell growth-inhibitory effect of an autophagy inducer by caspase-dependent apoptosis and caspase-independent cell death via autophagy and endonuclease G in leukemic cells.
- Published
- 2018
40. Follow-up of a randomised phase II study of chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: impact on allogeneic haematopoietic stem cell transplantation
- Author
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Naoya Taira, Kensei Tobinai, Yoshio Saburi, Atae Utsunomiya, Ilseung Choi, Hiroshi Fujiwara, Kenji Ishitsuka, Yukiyoshi Moriuchi, Ryuzo Ueda, Takashi Ishida, Tatsuro Jo, Yukio Kobayashi, Youko Suehiro, Kazunori Imada, Shinichiro Yoshida, Kisato Nosaka, Shigeki Takemoto, Hitoshi Suzushima, Makoto Yoshimitsu, Kenichi Yoshimura, Kazuhito Yamamoto, Takeshi Takahashi, and Koji Kato
- Subjects
Oncology ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Hematology ,Hematopoietic stem cell transplantation ,Transplantation ,03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Monoclonal ,Mogamulizumab ,Medicine ,Stem cell ,business ,030215 immunology ,medicine.drug - Published
- 2018
41. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma
- Author
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Tetsuichi Yoshizato, Masao Matsuoka, Kotaro Shide, Wataru Munakata, Makoto Yoshimitsu, Kenichi Yoshida, Hiromichi Suzuki, Kenji Ishitsuka, Hidehiro Itonaga, Hiroko Tanaka, Osamu Nureki, Yasunobu Nagata, Yoko Kubuki, Ryohei Ishii, Tatsuhiro Shibata, Kenichi Chiba, Kazuya Shimoda, Yotaro Ochi, Yasushi Miyazaki, Kosuke Aoki, Kisato Nosaka, Masashi Sanada, Seishi Ogawa, Aiko Sato-Otsubo, Tsuyoshi Nakamaki, Satoru Miyano, Akifumi Takaori-Kondo, Atae Utsunomiya, Keisuke Kataoka, Yusuke Sato, Yusuke Shiozawa, Toshiki Watanabe, Yuichi Shiraishi, Masakatsu Hishizawa, Masako Iwanaga, Ken Ishiyama, Jun-ichirou Yasunaga, Tomonori Hidaka, Shuichi Miyawaki, Takuro Kameda, Yoshitaka Imaizumi, Kensei Tobinai, and Akira Kitanaka
- Subjects
Adult ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lymphoma ,Immunology ,Single-nucleotide polymorphism ,Biology ,Biochemistry ,Gene dosage ,Adult T-cell leukemia/lymphoma ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,CDKN2A ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Epigenetics ,Genotyping ,Lymphoid Neoplasia ,Cell Biology ,Hematology ,Prognosis ,medicine.disease ,Leukemia ,030104 developmental biology ,030220 oncology & carcinogenesis - 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.
- Published
- 2018
42. Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma
- Author
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Makoto Yoshimitsu, Yasuyuki Kakurai, Toyotaka Kawamata, Kensei Tobinai, Koji Izutsu, Atae Utsunomiya, Kenji Ishitsuka, Hiroo Katsuya, Shinya Rai, Kisato Nosaka, Hironori Yamada, Takaaki Ono, Satoko Morishima, Kentaro Yonekura, Jun Ishikawa, Kunihiro Tsukasaki, Masaya Tachibana, Shinichi Makita, Shigeru Kusumoto, Kazunobu Kato, and Nobuaki Adachi
- Subjects
business.industry ,Immunology ,EZH2 ,Cancer research ,Phases of clinical research ,Medicine ,In patient ,Cell Biology ,Hematology ,Refractory Adult T-Cell Leukemia/Lymphoma ,business ,Biochemistry - Abstract
Background: Enhancer of zeste homolog 2 (EZH2) and its close homolog, EZH1, catalyze the attachment of 3 methyl groups to histone H3 at lysine 27 (H3K27me3). H3K27me3 is an epigenetic mark involved in downregulating gene expression associated with tumor suppression and cell differentiation. Recent evidence suggests that adult T-cell leukemia/lymphoma (ATL) can be driven by epigenetic dysregulation (Blood. 2016;127:1790-1802). Specifically, altered EZH2 expression has been implicated in the development and progression of ATL. Valemetostat tosylate (DS-3201b; valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that has demonstrated antitumor activity against hematologic malignancies, especially T-cell lymphoma, including relapsed or refractory (R/R) ATL in a phase 1 study (EHA 2021. Abstract S218). Here, we report the results from the primary analysis of a pivotal phase 2 study of valemetostat in Japanese patients (pts) with R/R ATL. Aims: This multicenter, single-arm, open-label, phase 2 study (NCT04102150) evaluated the efficacy and safety of single-agent valemetostat in pts with R/R ATL. The primary objective was to evaluate efficacy by central efficacy assessment committee (EAC)-assessed overall response rate (ORR), defined as the proportion of pts whose best response was complete remission (CR), uncertified CR, or partial remission using international consensus criteria (J Clin Oncol. 2009;27:453-59). The null hypothesis was an ORR of ≤5% (binomial test with a 1-sided significance level of 5%). Secondary outcome measures included CR rate, duration of response (DOR) per EAC, efficacy per investigator (INV) assessment, and the safety and pharmacokinetics of valemetostat. Methods: Pts ≥20 years of age with R/R ATL (acute, lymphomatous, or unfavorable chronic type) were enrolled from 24 sites in Japan. Pts must have had a positive antihuman T-cell leukemia virus type 1 antibody serum test and received prior therapy with mogamulizumab or ≥1 prior systemic therapy in the case of intolerance of, or contraindication for, mogamulizumab. Pts with prior allogeneic hematopoietic stem cell transplant were excluded. Valemetostat 200 mg was orally administered once daily in continuous 28-day cycles until disease progression or intolerance. The EAC-determined efficacy assessment was based on central evaluation of radiographic images and clinical data, including peripheral blood, skin, and bone marrow lesions (J Clin Oncol. 2009;27:453-59). Results: At the time of data cutoff (April 24, 2021), the study enrolled the planned 25 pts which included 16, 6, and 3 pts with acute, lymphomatous, or unfavorable chronic ATL subtypes, respectively. The median age was 69 years (range, 59-84 years). The median number of prior lines of therapy was 3 (range, 1-8). 24 pts (96.0%) had prior treatment with mogamulizumab. The study met its primary endpoint: with a median follow-up of 28 weeks (range, 14-71 weeks), valemetostat resulted in a 48% (12/25) ORR per EAC assessment (P 8 of 25 pts (32%) remained on treatment. 25 pts (100%) experienced ≥1 treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 15 pts (60%), and grade ≥3 serious TEAEs occurred in 6 pts (24%); valemetostat was not associated with any deaths. Dose interruption or reduction due to TEAEs occurred in 5 (20%) and 2 (8%) pts, respectively. Two pts (8%) discontinued due to TEAEs. The most common TEAEs (≥30% of pts) were platelet count decreased (80%), dysgeusia (36%), anemia (48%), and alopecia (40%); grade ≥4 platelet count decreased occurred in 3 pts (12%). Summary/Conclusions: Valemetostat resulted in a high response rate and durable antitumor effect in Japanese pts with R/R ATL, the majority of whom were pretreated with mogamulizumab. Valemetostat's safety profile was manageable. These results are consistent with those observed in the phase 1 study conducted in Japan and the US, suggesting that valemetostat could be a new treatment option for pts with R/R ATL. Valemetostat is also being evaluated in a global phase 2 study in pts with R/R ATL and R/R peripheral T-cell lymphoma (NCT04703192). Figure 1 Figure 1. Disclosures Yoshimitsu: Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Izutsu: Kyowa Kirin: Honoraria, Research Funding; Incyte: Research Funding; Chugai: Honoraria, Research Funding; Bayer: Research Funding; Beigene: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; AbbVie: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; MSD: Research Funding; Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Pfizer: Research Funding; Symbio: Honoraria, Research Funding; Allergan Japan: Honoraria; FUJI FILM Toyama Chemical: Honoraria. Makita: Takeda: Consultancy, Honoraria; SymBio: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Consultancy; CSL Behring: Honoraria; Chugai: Honoraria; BMS: Consultancy, Honoraria. Nosaka: Eisai Co., Ltd: Honoraria; Celgene K.K.: Honoraria; Kyowa Kirin Co., Ltd: Consultancy, Honoraria, Research Funding; Meiji Seika Parma Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Bristol Myers Squibb: Honoraria. Utsunomiya: Novartis Pharma: Honoraria; Kyowa Kirin: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen Pharmaceutical: Honoraria; JIMRO: Honoraria; Meiji Seika Pharma: Honoraria; Otsuka Medical Devices: Honoraria. Kusumoto: Daiichi Sankyo: Research Funding; Chugai: Honoraria, Research Funding; Kyowa Kirin: Honoraria. Tsukasaki: Solasia Pharma: Consultancy; Meiji Seika Pharma: Consultancy; Yakuruto: Consultancy; HUYABIO: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Takeda: Honoraria; Kyowa-hakko/Kirin: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Byer: Research Funding; Chugai Pharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Ono: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Rai: Chugai Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau. Yamada: Daiichi Sankyo: Current Employment. Kato: Bristol Myers Squibb: Current equity holder in publicly-traded company; Daiichi Sankyo: Current Employment. Tachibana: Daiichi Sankyo: Current Employment. Kakurai: Daiichi Sankyo: Current Employment. Adachi: Daiichi Sankyo: Current Employment. Tobinai: Celgene: Consultancy, Honoraria; Chugai Pharmaceutical: Honoraria; Eisai: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; HUYA Bioscience International: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria; Solasia Pharma: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria; Yakult: Honoraria; Zenyaku Kogyo: Consultancy, Honoraria. Yonekura: AbbVie: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Eisai: Honoraria; Eli Lilly Japan: Honoraria; Janssen Pharmaceuticals: Honoraria; Kaken Pharmaceutical: Honoraria; Kyowa Kirin: Honoraria; Maruho: Honoraria; Minophagen Pharmaceutical: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Taiho Pharmaceutical: Honoraria; Torii Pharmaceutical: Honoraria; UCB Japan: Honoraria. Ishitsuka: Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees.
- Published
- 2021
43. A Global Phase 2 Study of Valemetostat Tosylate (Valemetostat) in Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL), Including R/R Adult T-Cell Leukemia/Lymphoma (ATL) - Valentine-PTCL01
- Author
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Kazunobu Kato, Yining Du, Francine M. Foss, Jin Jin, Steven M. Horwitz, Kenji Ishitsuka, Ai Inoue, Koji Izutsu, and Pierluigi Porcu
- Subjects
business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Adult T-cell leukemia/lymphoma ,Peripheral T-cell lymphoma ,Refractory ,medicine ,Cancer research ,In patient ,business - Abstract
Background Enhancer of zeste homolog 2 (EZH2) and its close homolog, EZH1, catalyze the attachment of 3 methyl groups to histone H3 at lysine 27 (H3K27me3). H3K27me3 is an epigenetic marker involved in downregulating gene expression associated with tumor suppression and cell differentiation. Both altered EZH2 expression and EZH1's compensatory activity have been implicated in the development and progression of non-Hodgkin lymphomas (NHLs), including PTCL and ATL. R/R PTCL and ATL are associated with inferior outcomes, and many patients (pts) are not eligible for potentially curative transplants. Valemetostat tosylate (DS-3201b; also known as valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. A first-in-human phase 1 study was conducted for pts with R/R NHL in Japan and the US. Valemetostat demonstrated clinical antitumor activity in pts with NHL, including R/R PTCL and R/R ATL. Treatment with valemetostat 150 or 200 mg/day led to overall response rates (ORRs) of 54.5% (95% CI, 38.8%-69.9%) and 57.1% (95% CI, 28.9%-82.3%) in pts with R/R PTCL (n=44) or R/R ATL (n=14), respectively (EHA 2021. Abstract S218). Durability of response was demonstrated by a median duration of response (DOR) of 56.0 weeks (range, 44.43- -) in PTCL pts. Based on these encouraging efficacy results, a global phase 2 study was designed. Methods VALENTINE-PTCL01 (NCT04703192) is a global, multicenter, open-label, single-arm, noncomparative, 2-cohort, phase 2 study designed to evaluate the efficacy and safety of valemetostat monotherapy in adult pts with R/R PTCL or R/R ATL. Pts with R/R PTCL or R/R ATL are independently enrolled in cohort 1 or 2, respectively (Figure). Eligibility for both cohorts is determined based on a diagnosis made by a local pathologist/investigator and is centrally confirmed. Pts eligible for cohort 1 must have 1 of the following R/R PTCL subtypes: (1) angioimmunoblastic T-cell lymphoma, (2) follicular T-cell lymphoma, (3) nodal PTCL with T-follicular helper (TFH) phenotype, (4) PTCL not otherwise specified, (5) ALK-positive anaplastic large cell lymphoma (ALCL), (6) ALK-negative ALCL, (7) enteropathy-associated T-cell lymphoma, (8) monomorphic epitheliotropic intestinal T-cell lymphoma, (9) hepatosplenic T-cell lymphoma, (10) primary cutaneous γ-δ T-cell lymphoma, or (11) primary, cutaneous, CD8+, aggressive, epidermotropic, cytotoxic T-cell lymphoma. Pts must have ≥1 measurable lesion as assessed by computed tomography (CT). Pts eligible for cohort 2 must have acute, lymphomatous, or unfavorable, chronic-type R/R ATL with evaluable abnormal lymphocytes in the peripheral blood and skin lesions. Pts in both cohorts must have received ≥1 prior line of systemic therapy and have adequate organ function prior to the first dose of valemetostat. Pts with ALCL must have received prior brentuximab vedotin treatment. Pts who progressed after autologous or allogeneic hematopoietic cell transplant are eligible. Biomarker positivity (eg, EZH2 mutation) is not required for inclusion. Pts with active central nervous system involvement are excluded. Valemetostat 200 mg/day is administered orally once daily until disease progression or unacceptable toxicity occurs. The primary endpoint is ORR with valemetostat monotherapy as assessed by blinded independent central review. Pts in cohort 1 will be assessed by CT response criteria according to the 2014 Lugano criteria (J Clin Oncol. 2014;32:3059-68). Pts in cohort 2 will be assessed by the modified 2009 ATL criteria stemming from an international consensus meeting (J Clin Oncol. 2009;27:453-59). Secondary endpoints include DOR, complete response (CR) rate, duration of CR, partial response rate, progression-free survival, overall survival, pharmacokinetics, and safety and tolerability of valemetostat. Safety endpoints include treatment-emergent adverse events (TEAEs); TEAEs of special interest; serious TEAEs; fatal events; TEAEs leading to treatment discontinuation, interruption, or reduction; laboratory assessments; vital signs; and electrocardiogram analyses. VALENTINE-PTCL01 is currently recruiting at multiple sites in North America, Europe, Asia, and Oceania. Figure. VALENTINE-PTCL01 Study Design Figure 1 Figure 1. Disclosures Foss: Daiichi Sankyo: Honoraria; Kura: Honoraria; Acrotech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Kyowa: Honoraria; Mallinckrodt: Honoraria. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Izutsu: Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Beigene: Research Funding; Chugai: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Pfizer: Research Funding; Symbio: Honoraria, Research Funding; Allergan Japan: Honoraria; FUJI FILM Toyama Chemical: Honoraria. Ishitsuka: Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Astellas Pharma: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Kato: Daiichi Sankyo: Current Employment; Bristol Myers Squibb: Current equity holder in publicly-traded company. Jin: Daiichi Sankyo: Current Employment, Current equity holder in publicly-traded company. Du: Daiichi Sankyo: Current Employment; Incyte: Other: Spouse's current employer; Nektar Therapeutics: Ended employment in the past 24 months. Inoue: Daiichi Sankyo: Current Employment.
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- 2021
44. Hematologic Malignancies (HM)-Screen-Japan 01: A Mutation Profiling Multicenter Study on Patients with Acute Myeloid Leukemia
- Author
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Nobuyuki Aotsuka, Akihiko Gotoh, Seiichiro Katagiri, Yosuke Minami, Yukinori Nakamura, Naoko Hosono, Junichiro Yuda, Takaaki Ono, Makoto Yoshimitsu, Takeshi Kondo, Takanobu Morishita, Kenji Ishitsuka, Satoshi Iyama, Tsutomu Kobayashi, Nobuhiko Yamauchi, Naoto Takahashi, Junya Kuroda, Hirohiko Shibayama, Motoki Eguchi, Suguru Fukuhara, Koji Izutsu, Takahiro Yamauchi, Masamitsu Yanada, Makoto Nakamura, Reiki Ogasawara, Yoshikazu Utsu, Kensuke Usuki, Kentaro Fukushima, Kazuhito Yamamoto, and SungGi Chi
- Subjects
Oncology ,medicine.medical_specialty ,Mutation profiling ,Multicenter study ,business.industry ,Internal medicine ,Immunology ,medicine ,Myeloid leukemia ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: Recently, whole exome sequencing has been used for the next-generation sequencing of acute myeloid leukemia (AML), and certain gene mutations have been identified in patients with AML. The treatment strategies for leukemia have undergone drastic changes with the rapid development of new drugs. However, the proper use of newly developed agents poses a major challenge in AML treatment. Genome profiling analysis can be used to select the optimal treatment for patients with newly diagnosed AML. Methods and Results: Hematologic malignancies (HM)-SCREEN-Japan 01 is an actionable mutation profiling multicenter study of patients with newly diagnosed AML who cannot be treated with first standard treatment or patients who have relapsed/refractory AML (R/R-AML). The objective of this study was to evaluate the frequency and characteristics of cancer-related genomic alterations in patients with AML using a comprehensive genome profiling assay (FoundationOne®Heme (F1H)) and determine the quality of specimens used in gene analysis. Before participant recruitment, approval was obtained from the institutional review board at each participating institution. The trial was registered in the UMIN Clinical Trials Registry (UMIN000035233). This study was conducted at 17 participating institutions and had a sample size of 200. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) fulfillment of either of the following conditions: i) newly diagnosed AML unfit for standard treatment (ND-unfit AML) or ii) R/R-AML; 3) sufficient sample collection via bone marrow aspiration; 4) Age of participants 20 years or above during registration; 5) provision of written informed consent by participants. The primary outcome was the frequency of each genomic alteration, as determined using F1H, which is a comprehensive genome profiling test based on next-generation sequencing, in the AML specimens. The secondary outcome was the association between each genomic alteration and the clinicopathological characteristics, prognosis, and quality of specimens used in the genetic analysis. Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating AML. One hundred and eighty-two patients were recruited, and the F1H report was successfully obtained for 177 patients (97.3%). The median age of the 66 patients with ND-unfit AML was 73 years (63-79 years), and that of the 105 patients with R/R-AML was 50 years (41-68 years). The median turnaround time was 13 days (minimum 8 days). Recurrent alterations were observed in FLT3 (28.7%), TP53 (21.6%), RUNX1 (20.5%), DNMT3A (18.7%), NPM1 (18.7%), ASXL1 (15.2%), TET2 (14.0%), KMT2A-rearrangement (13.5%), and NRAS (13.5%). IDH1 and/or IDH2 mutations were identified in specimens collected from 30 patients (17.5%). Compared with the prevalence in 2247 patients with AML in the US and Europe who underwent F1H analysis, the frequencies of mutations in FLT3 (28.7% vs. 20.5%) and TP53 (21.6% vs. 17.0%) were higher in this Japanese cohort. Mutations in IDH2, PTPN11, and SF3B1 were observed along with KMT2A rearrangement. Mutations in TP53 tended to be exclusive to the FLT3 mutation. In comparison between the ND-unfit AML and R/R-AML, mutations in TET2 and ASXL1 tended to be more frequnt in ND-unfit AML (17.9% vs. 7.0%, p=0.038, 18.9% vs. 8.5%, p=0.055, respectively). The median expression level of WT1 mRNA at the time of sample collection was 4,490 copies/μgRNA (n=158), and WT1 mutation was frequently found in the WT1-high expression group (13.9% vs. 3.8%, p=0.03), suggesting that the mutation of WT1 may cause overexpression of WT1 as an oncogene. Conclusions: In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified leukemia-associated genes that can be used as therapeutic targets in AML, which have rarely been identified thus far. Figure 1 Figure 1. Disclosures Yamauchi: Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Shibayama: Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Avvie: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Essentia Pharma Japan: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Fujimoto: Honoraria; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Mundi Pharma: Honoraria. Kondo: Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho: Consultancy. Yamamoto: Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; Daiichi Sankyo: Honoraria; Chugai: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Kuroda: Sanofi: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding. Yoshimitsu: Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Ishitsuka: Eli Lilly: Research Funding; Mochida: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Huya Japan: Other: Personal fees. Ono: DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Toyamakagaku: Research Funding; Eizai: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Iyama: Otsuka: Honoraria, Research Funding; Novartis: Honoraria; Nippon Shinyaku: Honoraria; MSD: Research Funding; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Daiichi Sankyo: Honoraria; CSL Behring: Honoraria; Astellas: Honoraria; Alexion Pharmaceuticals: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Yakult: Research Funding; Takeda: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Genmab: Honoraria, Research Funding; Huya Biosciences: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.
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- 2021
45. Genomic Analysis of NPM1 Mutation and KMT2A(MLL)-Rearrangement/Amplification in Japanese Patients with Acute Myeloid Leukemia: Hematologic Malignancies (HM)-Screen-Japan 01
- Author
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Naoko Hosono, Takaaki Ono, Takeshi Kondo, Tsutomu Kobayashi, Akihiko Gotoh, Kentaro Fukushima, Kensuke Usuki, SungGi Chi, Kenji Ishitsuka, Seiichiro Katagiri, Kazuhito Yamamoto, Yukinori Nakamura, Kaoru Yamamoto, Makoto Yoshimitsu, Takahiro Yamauchi, Suguru Fukuhara, Hiroto Horiguchi, Nobuhiko Yamauchi, Yoshikazu Utsu, Hirohiko Shibayama, Koji Izutsu, Junya Kuroda, Makoto Nakamura, Junichiro Yuda, Takanobu Morishita, Yasuyuki Nagata, Reiki Ogasawara, Nobuyuki Aotsuka, Yoshimasa Kamoda, Motoki Eguchi, Yosuke Minami, Naoto Takahashi, Kensuke Kojima, Masamitsu Yanada, Satoshi Iyama, and Naohito Fujishima
- Subjects
biology ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Mll rearrangement ,Biochemistry ,NPM1 Mutation ,KMT2A ,Cancer research ,biology.protein ,Medicine ,business - Abstract
Background and Methods: NPM1 mutation and KMT2A(MLL)-rearrangement/amplification are present in approximately 27% and 8.5% patients with acute myeloid leukemia (AML), respectively (data from cBioPortal). Although they have different clinical features and prognostic impact, recent studies suggest that the MLL co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). However, the real-world epidemiology of these mutations and co-existing gene alterations have not been thoroughly investigated in Japan. We launched an actionable mutation profiling multicenter study entitled Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233). In this study, a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel for patients with relapsed/refractory (R/R) AML as well as patients with newly-diagnosed (ND) AML who are ineligible for standard chemotherapy. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. Results: One-hundred-eighty-two patients were recruited in this study and the F1H report was successfully returned in 177 patients (97.3%). Median age of 68 patients with ND-AML was 73 [63-79] years and those of 109 patients with R/R-AML was 50 [40-68.5] years. Median turn-around time was 13 days (minimum 8 days).We found 32 patients (18.1%) with NPM1 mutation and 23 patients (13.0%) of KMT2A(MLL)-rearrangement/amplification out of the 177 patients. These two alterations were mutually exclusive in this study. The median age of patients with NPM1 mutation (NPM1 mt.) and KMT2A-rearrangement (KMT2A-r) were 56.5 [43.5-73.8] and 62 [45-71] years, respectively. Three quarters or more patients were R/R-AML in both groups. WT1 expression levels were much higher in patients with NPM1 mt. than the other group (6,000 [77-110,000] vs. 93 [34-5,800] copies/mcgRNA). The major amino acid alteration of NPM1 was a frameshift mutation at the 288 th histidine (W288fs*12). Patterns of KMT2A(MLL)-rearrangement included MLL fusion (e.g., MLL-MLLT3) and partial tandem duplication (PTD) in ten patients each. MLL amplification was observed in three patients. Frequently co-occurring mutations with NPM1 mt. included FLT3 (56.3%), DNMT3A (46.9%), TET2 (34.4%), WT1 (18.8%), IDH1 (18.8%), and IDH2 (15.6%). Those with KMT2A-r included FLT3 (39.1%), TP53 (26.1%), PTPN11 (21.7%), DNMT3A (17.4%), and IDH2 (17.4%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS, PTPN11, and NF1) were observed in five patients with NPM1 mt. (15.6%) and 11 patients (47.8%) with KMT2A-r. None of the six patients with TP53 mutation had NPM1 mutation. The prognostic impact of each genes is currently being analyzed. Conclusions: Approximately three in ten patients with AML had NPM1 mutation and/or KMT2A(MLL)-rearrangement/amplification. No single patient had both the alterations. FLT3 and DNA methylation-associated genes (e.g., DNMT3A and TET2) were frequently seen in patients with NPM1 mt. In contrast, TP53 and RAS pathway-related gene alterations (e.g., NRAS, KRAS, PTPT11 and NF1) were relatively dominant in patients with KMT2A-r. TP53 mutation seemed unlikely to occur along with NPM1 mutation. Figure 1 Figure 1. Disclosures Shibayama: Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Avvie: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Essentia Pharma Japan: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Fujimoto: Honoraria; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Mundi Pharma: Honoraria. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria, Research Funding. Kuroda: Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Mundipharma: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; Celgene: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Fujishima: Pfizer: Speakers Bureau. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Symbio: Honoraria; Takeda: Honoraria, Research Funding; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.
- Published
- 2021
46. Genomic Analysis Focusing on RUNX1-RUNX1T1 in Japanese Patients with AML: HM-Screen-Japan 01
- Author
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Daigo Akahane, Yoshikazu Utsu, Yukinori Nakamura, Kensuke Usuki, Makoto Nakamura, Makoto Yoshimitsu, Kenji Ishitsuka, Junya Kuroda, SungGi Chi, Koji Izutsu, Reiki Ogasawara, Masamitsu Yanada, Nobuyuki Aotsuka, Seiichiro Katagiri, Yosuke Minami, Takahiro Yamauchi, Hirohiko Shibayama, Naoto Takahashi, Akihiko Gotoh, Tsutomu Kobayashi, Nobuhiko Yamauchi, Takanobu Morishita, Motoki Eguchi, Kentaro Fukushima, Naoko Hosono, Takaaki Ono, Takeshi Kondo, Satoshi Iyama, Junichiro Yuda, and Kazuhito Yamamoto
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,Runx1 runx1t1 ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background and Methods: Acute myeloid leukemia (AML) bearing the RUNX1-RUNX1T1 fusion gene is known to be one of the core-binding factor AML (CBF-AML) which exerts relatively good prognosis. The RUNX1-RUNX1T1 fusion gene are present in approximately 3.5% of patients with AML (data from cBioPortal). However, the real-world epidemiology of this mutation and co-existing gene alterations have not been fully investigated in Japan. We launched an actionable mutation profiling multicenter study named Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel for patients with relapsed/refractory (R/R) AML as well as patients with newly-diagnosed (ND) AML who were ineligible for standard chemotherapy. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. Results: We found 12 patients (6.8%) with the RUNX1-RUNX1T1 fusion gene out of 177 patients who joined this study and the F1H report was successfully retuned. Eight of these patients were enrolled as R/R AML and four were enrolled as ND AML who are ineligible for standard chemotherapy. Four (50%) of R/R patients were received allogeneic hematopoietic stem cell transplantation. Among the 12 patients with the RUNX1-RUNX1T1 fusion gene, eight (66.7%) had KIT mutation. The major amino acid alteration of KIT was D816V/Y and two patients had two different point-mutations of KIT (one with D816Y plus D816V and the other with D816V plus N822K). No particular mutations, other than KIT, were predominantly co-occurred with RUNX1-RUNX1T1 fusion gene. Especially in R/R patients, 75 % of them had the KIT mutation. Two R/R patients without the KITmutation had JAK2 V617F and FLT3 D835Y respectively. Conclusions: AML with RUNX1-RUNX1T1 fusion gene is currently not indicated for transplantation in the first remission. Previous studies have demonstrated that approximately 30% of patients with CBF-AML harbored the KIT mutations at diagnosis, which might be an indicator of poor prognosis. In our study, the KIT mutations were detected much more frequently than in previously studies of newly-diagnosed CBF-AML. This result may suggest that patients with the KIT mutations were concentrated because our study targeted AML patients who were R/R to prior therapy or ineligible for standard chemotherapy. In addition, no specific mutations highly related to the RUNX1-RUNX1T1 fusion gene were detected other than the KIT mutation, suggesting the KIT mutation might be a suitable molecular marker to predict poor prognosis in AML with the RUNX1-RUNX1T1 fusion gene. Our study revealed the importance of KIT mutations in patients with R/R AML with RUNX1-RUNX1T1 fusion gene, and that the KITmutations may be a promising therapeutic target for this population. Furthermore, it is interesting that driver mutations such as JAK2 and FLT3 mutation were detected in R/R patients without KIT mutation, although further investigation is needed. This suggests that comprehensive genomic assays are highly useful in establishing precision medicine, even in this type of AML, which is generally considered to have a good prognosis. Since most of R/R patients need allo-SCT, precision medicine targeting KIT may be considered for post-recurrence treatment in AML with RUNX1-RUNX1T1 fusion gene, such as bridge therapy to transplantation, in the future. Figure 1 Figure 1. Disclosures Shibayama: Janssen Pharmaceutical K.K.: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Fujimoto Pharmaceutical Corp.: Speakers Bureau; Daiichi Sankyo Co., Ltd.: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca K.K.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia Japan KK: Research Funding; Eisai Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Bristol-Myers Squibb K.K.: Speakers Bureau. Yamauchi: Daiichi Sankyo: Research Funding; Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Solasia Pharma: Research Funding. Kondo: Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy. Yamamoto: IQIVA/Incyte: Research Funding; AstraZeneca: Honoraria, Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Chugai: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Kuroda: Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Yoshimitsu: Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Ishitsuka: BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; MSD: Research Funding; Teijin Pharma: Research Funding; Otsuka Pharmaceutical: Other: Personal fees; Shire: Other; Mochida: Other: Personal fees, Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: Novartis Pharma KK: Honoraria; Merck Sharp & Dohme: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Toyamakagaku: Research Funding; Eizai: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Iyama: Novartis: Honoraria; Nippon Shinyaku: Honoraria; MSD: Research Funding; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Daiichi Sankyo: Honoraria; CSL Behring: Honoraria; Astellas: Honoraria; Alexion Pharmaceuticals: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Celgene: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Beigene: Research Funding; Chugai: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Pfizer: Research Funding; Symbio: Honoraria, Research Funding; Allergan Japan: Honoraria; FUJI FILM Toyama Chemical: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.
- Published
- 2021
47. Properties and Distribution of IDH-1/2 Mutations in Acute Myeloid Leukemia By the Comprehensive Genomic Analysis
- Author
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Kenji Ishitsuka, Motoki Eguchi, Yosuke Minami, Reiki Ogasawara, Takahiro Yamauchi, Hirohiko Shibayama, Makoto Yoshimitsu, SungGi Chi, Satoshi Uchiyama, Naoto Takahashi, Masamitsu Yanada, Nobuyuki Aotsuka, Junichiro Yuda, Nobuhiko Yamauchi, Satoshi Iyama, Tsutomu Kobayashi, Makoto Nakamura, Kensuke Usuki, Yukinori Nakamura, Kentaro Fukushima, Seiichiro Katagiri, Nakamura Hirotaka, Kazuhito Yamamoto, Takanobu Morishita, Junya Kuroda, Akihiko Gotoh, Naoko Hosono, Takaaki Ono, Takeshi Kondo, Suguru Fukuhara, and Koji Izutsu
- Subjects
Immunology ,Cancer research ,Distribution (pharmacology) ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,Biochemistry - Abstract
Background: Isocitrate dehydrogenase (IDH)-1 and -2 are TCA cycle-involved enzymes which convert isocitrate to alpha-ketoglutarate. Mutations that alter the enzymatic activity causes accumulation of a mal-metabolite D-2-hydroxyglutarate, which results in inhibition of DNA methylation and tumorigenesis. IDH-1 and IDH-2 mutation are present in approximately 7-10% and 10% of patients with acute myeloid leukemia (AML), respectively. Recently, whole exome sequencing has been used for the next-generation sequencing of AML, and certain gene mutations have been identified in patients with AML. The treatment strategies for leukemia have undergone drastic changes with the rapid development of new drugs. However, the proper use of newly developed agents poses a major challenge in AML treatment. Genome profiling analysis can be used to select the optimal treatment for patients with newly diagnosed AML. IDH mutant-specific inhibitors such as ivosidenib and enasidenib were already approved in the US, and combination treatment with venetoclax and Azacitidine was recently approved in Japan. Methods and Results: We lunched an actionable mutation profiling multicenter study named Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel. The primary outcome was the frequency of each genomic alteration, as determined using F1H, which is a comprehensive genome profiling test based on next-generation sequencing, in the AML specimens. The secondary outcome was the association between each genomic alteration and the clinicopathological characteristics, prognosis, and quality of specimens used in the genetic analysis. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) fulfillment of either of the following conditions: i) newly diagnosed AML unfit for standard treatment (ND-unfit AML) or ii) R/R-AML; 3) sufficient sample collection via bone marrow aspiration; 4) Age of participants 20 years or above during registration; 5) provision of written informed consent by participants. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. The median turnaround time was 13 days (minimum 8 days). We found 13 patients (7.3%) with IDH1 mutation and 17 patients (9.6%) with IDH2 mutation out of 177 patients who joined this study and the F1H report was successfully returned. Only one patient had both mutations, and each mutation was mutually exclusive in all the other patients (Figure 1). The major amino acid alteration of IDH1 and IDH2 were R132C/G/H/L and R140Q/W, respectively. Frequently co-occurring mutations include FLT3 (44.8%), NPM1 (34.5%), DNMT3A (31.0%) and RUNX1 mutation (20.7%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS and PTPN11) were seen in 6 patients (20.7%). Any gene alterations didn't show statistically significant co-occurrence with IDH1 and IDH2 mutation. Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating FLT3-mutated AML. Also in this cohort, we are examining the properties and distribution of IDH1/2 mutations during treatment with FLT3 inhibitors. In the several patients, expansion and persistence of IDH mutated clones seemed to be cause of resistance (Figure 2 as the representative result). The detailed clinical outcomes of AML patients with IDH1/2 mutations are under investigation. Conclusions: In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified IDH-1/2 mutation that can be used as therapeutic targets in AML, which have rarely been identified thus far. Figure 1 Figure 1. Disclosures Shibayama: Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Fujimoto: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Mundi Pharma: Honoraria; Essentia Pharma Japan: Research Funding. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria. Kuroda: Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Nippon Boehringer Ingelheim: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Asahi kasei: Research Funding; Eli Lilly: Research Funding; MSD: Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Kyowa Kirin: Other: Personal fees, Research Funding; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Huya Japan: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding. Ono: Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Eizai: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Genmab: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Chugai: Honoraria, Research Funding; Symbio: Honoraria; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Minami: Novartis Pharma KK: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; CMIC: Research Funding.
- Published
- 2021
48. Clinical Significance of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01
- Author
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Kentaro Fukushima, Yukinori Nakamura, Satoshi Iyama, Naoko Hosono, Takaaki Ono, Akihiko Gotoh, Kazuhito Yamamoto, Masamitsu Yanada, Takanobu Morishita, Junya Kuroda, Makoto Yoshimitsu, Suguru Fukuhara, Koji Izutsu, Nobuhiko Yamauchi, Takeshi Kondo, Kensuke Usuki, SungGi Chi, Reiki Ogasawara, Junichiro Yuda, Takahiro Yamauchi, Tsutomu Kobayashi, Yosuke Minami, Hirohiko Shibayama, Yoshikazu Utsu, Naoto Takahashi, Makoto Nakamura, Nobuyuki Aotsuka, Seiichiro Katagiri, Yoshimasa Kamoda, Kenji Ishitsuka, and Motoki Eguchi
- Subjects
Oncology ,medicine.medical_specialty ,Multicenter study ,business.industry ,Internal medicine ,Immunology ,Flt3 mutation ,medicine ,Clinical significance ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background and Methods: FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD) are types of mutations present in approximately 30% of patients with acute myeloid leukemia (AML). Currently, FLT3 inhibitors (FLT3i) are available in clinical practice, and the second-generation FLT3i, gilteritinib and quizartinib, are being used in Japan. However, the actual epidemiology of FLT3 mutations and co-existing gene alterations, particularly resistance mechanisms after FLT3i treatment, have not been thoroughly investigated in a Japanese population. Therefore, we conducted an actionable mutation profiling multicenter study, Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed using the FoundationOne Heme (F1H) panel for patients with relapsed/refractory (R/R) AML and patients with newly diagnosed AML who were ineligible for standard chemotherapy (ND unfit). Paraffin-embedded bone marrow samples were used for next-generation sequencing (NGS) examination using the F1H panel. We analyzed the relationships between FLT3 gene mutations and other mutations and then chronologically evaluated the variant allele frequency (VAF) of gene mutations in the genomic profiles of patients with AML receiving FLT3i. Results: Of the 171 patients who participated in this study, 49 (28.7%) had FLT3 mutations. FLT3-ITD and FLT3-TKD accounted for 59% and 43% of all cases of FLT3 mutations, respectively. Two patients (4%) were found to have dual mutations: one with FLT3-ITD plus FLT3-TKD and another with FLT3-ITD plus FLT3-F691L. Eight patients (4.5%) were found to have the FLT3-N676K mutation, which is sensitive to gilteritinib but undetectable by currently available PCR-based companion diagnostic tools in Japan. Frequently co-occurring mutations included those of NPM1 (37%), DNMT3A (33%), IDH1/IDH2 (27%), WT1 (24%), and RUNX1 (22%). Mutations in RAS pathway-related genes (e.g., KRAS, NRAS, and PTPN11) were observed in 15 patients (31%). No gene alteration showed statistically significant co-occurrence with the FLT3mutation. However, the median number of mutations that co-exist with FLT3-TKD was slightly higher than that of FLT3-ITD (four genes [3-5] vs. three genes [2-5]). Sequential changes in the VAF of each gene alteration were investigated in nine patients with FLT3 mutations who eventually gained resistance to FLT3i. It was suggested that there were various patterns in clone evolution. Some showed the acquisition of not only CBL or NRAS as RAS pathways, but also other driver mutations: one showed a persistent FLT3mutation, one showed FLT3-ITD plus FLT3-TKD, and one showed a newly acquired FLT3 mutation substituting an existing FLT3 mutation. We also found that founder mutations, such as the DNMT3Amutation, remain even after eradication of FLT3 mutation during treatment with FLT3i, which could be the cause of the outcome of complete remission with incomplete hematologic recovery. Conclusions: This is the first report to analyze R/R and ND unfit AML cases in a Japanese cohort using F1H NGS, revealing a higher incidence of FLT3-ITD/TKD mutations than previously reported. Therefore, F1H mutational analyses for R/R and ND unfit AML patients harboring FLT3-ITD/TKD mutations may reveal novel therapeutic targets that are sensitive to FLT3i. Samples from these patients showed non-canonical gain-of-function mutations, such as N676K, S451F, V592D, and F691L, which could guide the selection of optimal anti-FLT3 therapies. In addition, longitudinal NGS analysis revealed clonal evolution in cases in which resistance to the FLT3i, gilteritinib and quizartinib were observed. Time-dependent analysis of allele frequencies can help evaluate the details of leukemia clonal evolution and provide optimal treatment options. Figure Legends Fig.1 Overview of gene mutations using F1H NGS analyses. The color of each column indicates the type of genetic mutation. Blue column; point mutation/insertion/deletion, green column; fusion gene, purple column; dual mutations. Fig.2 The chronological changes of leukemic cells fractions bearing each gene mutations during treatment with FLT3 inhibitors, gilteritinib and quizartinib. Figure 1 Figure 1. Disclosures Shibayama: Otsuka: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Nippon Shinyaku: Honoraria; Fujimoto: Honoraria; Daiichi Sankyo: Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Celgene: Research Funding; Mundi Pharma: Honoraria; Essentia Pharma Japan: Research Funding. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Astellas Pharma Inc.: Consultancy, Honoraria; SANWA KAGAKU KENKYUSHO CO.,LTD.: Consultancy. Yamamoto: IQIVA/Genmab: Research Funding; Micron: Honoraria; Zenyaku: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SymBio: Honoraria, Research Funding; Solasia Pharma: Research Funding; Sanofi: Honoraria; Otsuka: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Mundipharma: Research Funding; MSD: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria; Janssen: Honoraria; HUYA: Consultancy; IQIVA/HUYA: Honoraria; IQIVA/Incyte: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Chugai: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; ADC Therapeutics: Honoraria. Kuroda: Kyowa Kirin: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Eisai: Other: Personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; MSD: Research Funding; Teijin Pharma: Research Funding; Otsuka Pharmaceutical: Other: Personal fees; Shire: Other; Mochida: Other: Personal fees, Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Toyamakagaku: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Ono: Research Funding. Iyama: SymBio Pharmaceuticals: Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Izutsu: Allergan Japan: Honoraria; Symbio: Honoraria, Research Funding; Pfizer: Research Funding; Ono: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genmab: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Yakult: Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; FUJI FILM Toyama Chemical: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Novartis Pharma KK: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.
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- 2021
49. Genetic Features of AML with MLL-Rearrangement and NPM1 Mutation: An Interim-Analysis of HM-Screen-Japan 01
- Author
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Akihiko Gotoh, Satoshi Iyama, Naohito Fujishima, Suguru Fukuhara, Koji Izutsu, Ken-ichi Miyamoto, Seiichiro Katagiri, Naoko Hosono, Junya Kuroda, Takaaki Ono, Hiroto Horiguchi, Takeshi Kondo, Makoto Nakamura, Kentaro Fukushima, Yoshikazu Utsu, Makoto Yoshimitsu, Kenji Ishitsuka, Kazuhito Yamamoto, Yosuke Minami, Kazuto Togitani, Takanobu Morishita, Kanenari Takemura, Hirohiko Shibayama, Takahiro Yamauchi, SungGi Chi, Kensuke Kojima, Yasuyuki Nagata, Yukinori Nakamura, Nobuyuki Aotsuka, Naoto Takahashi, Motohito Okabe, Kensuke Usuki, Yoshimasa Kamoda, Kaoru Yamamoto, Tsutomu Kobayashi, Reiki Ogasawara, and Masamitsu Yanada
- Subjects
Genetics ,NPM1 Mutation ,Immunology ,Cell Biology ,Hematology ,Mll rearrangement ,Biology ,Interim analysis ,Biochemistry - Abstract
Background: Acute myeloid leukemias with KMT2A (formerly known as MLL-1) fusion genes (MLL-AML) and those with NPM1 mutations (NPM1-AML) are distinct subtypes as defined by the WHO classification. Although they have different clinical features and prognostic impact , recent studies suggest that the MLL1 co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). New targeted strategies for these AML subtypes are expected as preliminary data suggest that menin-MLL1 inhibition may inhibit malignancy. In addition to classical chromosomal analysis and prefixed fusion gene screening, next-generation sequencing (NGS) should help in identifying the precise prevalence of these alterations and understanding the relationship with other pathological mutations. We launched the HM-SCREEN-JAPAN01 study (UMIN000035233) in which gene alterations are analyzed by FoundationOne Heme® in patients with AML who are relapsed/refractory to, or ineligible for standard therapies. Aiming for 200 registrations, recruitment has reached approximately 100. The interim results are described here. Methods: HM-SCREEN-JAPAN01 is an observational study and conducted by 17 participating institutions. The eligibility criteria are as follows: 1) histological diagnosis of AML must be made by bone marrow testing; 2) one of the following conditions must be fulfilled: i) a patient with newly diagnosed AML and is ineligible for standard treatment, or ii) a patient with AML who has relapsed or is refractory to prior therapy; 3) sufficient amount of bone marrow sample must be available; 4) age at registration must be 20 or more; and 5) written informed consent must be taken. All samples were analyzed by FoundationOne Heme®. Results:Nine patients (9.9%) with MLL-AML and seventeen patients (18.7%) with NPM1-AML were found among 91 available cases (either one found in 28.6%). No patients demonstrated MLL-rearrangement and NPM1-mutation simultaneously. Median age of patients with MLL-AML (42-68 y) was a decade less than that of patients with NPM1-AML (55-74 y), and the majority of cases had a clinical relapse or were refractory to prior therapies. Translocations involving chromosome 11q23.3 (e.g. t(9;11)(p21.3;q23.3)) were found in 5 of 8 patients (62.5%) with MLL-AML (data not available due to insufficient cell count in one case) and no chromosomal abnormalities were detected in 10 of 16 patients (62.5%) with NPM1-AML (chromosomal analysis was not performed in one case). In patients with MLL-AML (see Figure), FLT3 mutations were found in 3 of 9 cases (33.3%), all of which were point mutations within the tyrosine kinase domain (FLT3-TKD). PTPN11 mutations were also found simultaneously in these three cases. Co-existing NRAS and TP53 mutations with high allele-frequency (32-50%) were also seen in two different cases. A targetable mutation of IDH2 was seen in one patient (11.1%) who had an FLT3 mutation with low allele-frequency (2%). In patients with NPM1-AML (see Figure), allele-frequency of mutated NPM1 ranged from 10 to 44%. Relatively common co-existing mutations were TET2 (7 of 17; 41.2%), DNMT3A (9 of 17; 52.9%), and FLT3 (9 of 17; 52.9%). Unlike in MLL-AML patients, all FLT3 alterations were internal tandem duplication (FLT-ITD) with one case of dual FLT3-ITD and -TKD mutation. IDH1 and IDH2 mutations were found in two (11.8%) and four (23.5%) separate cases, respectively. A rare fusion gene ETV6-NTRK3 (one of primary targets of NTRK inhibitors) was detected in one patient (5.9%) who had IDH1 mutation with moderate allele-frequency (17%). Conclusion: MLL-rearrangements and NPM1-mutations were found in approximately a quarter of the 91 AML patient (mostly relapsed or refractory) bone marrow samples analyzed. These alterations appeared to be mutually exclusive. FLT3 alterations were seen in a third of the MLL-AML cases and half of the NPM1-AML cases, seemingly more frequent than that previously reported. Interestingly, FLT3-TKDs were dominant in MLL-AML cases, whereas NPM1-AML cases carried FLT3-ITD. IDH1 and IDH2 mutations commonly co-existed in both groups. This HM-SCREEN-Japan01 study is now recruiting patients, and a further understanding of genomic distribution and correlation is expected. Figure Disclosures Yamauchi: Otsuka:Research Funding;Astellas:Research Funding;Daiichi Sankyo:Research Funding;Chugai:Honoraria;Pfizer:Honoraria, Research Funding;Abbie:Research Funding;Solasia Pharma:Research Funding;Ono Pharmaceutical:Honoraria.Shibayama:AstraZeneca:Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria;Pfizer:Honoraria;Fujimoto:Honoraria;Janssen:Honoraria, Research Funding;Teijin:Research Funding;Novartis:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Daiichi Sankyo:Honoraria;Chugai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Sumitomo Dainippon:Honoraria, Research Funding;Merck Sharp & Dohme:Research Funding;Shionogi:Research Funding;Astellas:Research Funding;Taiho:Research Funding;Otsuka:Honoraria;Bristol-Myers Squibb:Honoraria;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Eisai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Kyowa Kirin:Honoraria;Ono:Honoraria, Research Funding;Mundi Pharma:Honoraria.Yamamoto:Stemline Therapeutics:Consultancy;Meiji Seika Pharma:Consultancy, Honoraria;MSD:Consultancy, Honoraria, Research Funding;Chugai:Consultancy, Honoraria, Research Funding;Eisai:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Consultancy;IQIVA/HUYA:Honoraria;HUYA:Consultancy;IQIVA/Incyte:Research Funding;Mundipharma:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria;Mochida:Honoraria;Gilead Sciences:Research Funding;Solasia Pharma:Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Novartis:Honoraria, Research Funding;Ono:Consultancy, Honoraria, Research Funding;Aichi Cancer Center:Current Employment;AbbVie:Consultancy, Honoraria, Research Funding;Astra-Zeneca:Consultancy, Research Funding;Bayer:Research Funding;Bristol-Myers Squibb:Honoraria;Celgene:Consultancy, Honoraria, Research Funding;Zenyaku:Research Funding;Takeda:Consultancy, Honoraria, Research Funding;Yakult:Research Funding;SymBio:Research Funding;Pfizer:Honoraria;Otsuka:Consultancy, Honoraria, Research Funding;Sanofi:Honoraria;Sumitomo Dainippon:Honoraria;Janssen:Honoraria.Fujishima:Pfizer:Speakers Bureau.Takahashi:Pfizer Japan Inc.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria, Research Funding;Bristol-Myers Squibb Company:Honoraria.Usuki:Alexion:Speakers Bureau;Pfizer:Research Funding;Nippon Boehringer Ingelheim:Research Funding;Mundipharma:Research Funding;Astellas-Amgen-Biopharma:Research Funding;Nippon shinyaku:Research Funding, Speakers Bureau;Eisai:Speakers Bureau;MSD:Speakers Bureau;Takeda:Speakers Bureau;PharmaEssentia:Speakers Bureau;Yakult:Speakers Bureau;Symbio:Research Funding, Speakers Bureau;Daiichi Sankyo:Research Funding, Speakers Bureau;Sumitomo Dainippon:Research Funding;Otsuka:Research Funding, Speakers Bureau;Novartis:Research Funding, Speakers Bureau;Brisol-Myers Squibb:Research Funding, Speakers Bureau;Kyowa Kirin:Research Funding, Speakers Bureau;Ono:Research Funding, Speakers Bureau;Janssen:Research Funding;Celgene:Research Funding, Speakers Bureau;Takeda:Research Funding;Astellas:Research Funding, Speakers Bureau;Abbvie:Research Funding;Gilead:Research Funding.Ono:Celgene:Honoraria, Research Funding;Kyowa Kirin Co., Ltd.:Honoraria, Research Funding;Chugai Pharmaceutical Co., Ltd.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria;Mundipharma K.K.:Honoraria;TAIHO PHARMACEUTICAL CO., LTD.:Research Funding;Eisai Co., Ltd.:Honoraria;Otsuka Pharmaceutical Co., Ltd.:Honoraria;Astellas Pharma Inc.:Honoraria;Bristol-Myers Squibb Company:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda Pharmaceutical Company Limited.:Honoraria;ONO PHARMACEUTICAL CO., LTD.:Honoraria, Research Funding;DAIICHI SANKYO COMPANY, LIMITED.:Honoraria;Janssen Pharmaceutical K.K:Honoraria.Kuroda:Daiichi Sankyo:Honoraria, Research Funding;Pfizer:Honoraria, Research Funding;Sysmex:Research Funding;Janssen Pharmaceutical K.K:Consultancy;Eisai:Honoraria, Research Funding;Sanofi:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria, Research Funding;Otsuka Pharmaceutical:Honoraria, Research Funding;Ono Pharmaceutical:Honoraria, Research Funding;Abbvie:Consultancy, Honoraria;MSD:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Dainippon Sumitomo Pharma:Honoraria, Research Funding;Chugai Pharmaceutical:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Bristol-MyersSquibb:Consultancy, Honoraria, Research Funding;Astellas Pharma:Honoraria, Research Funding;Fujimoto Pharmaceutical:Honoraria, Research Funding;Taiho Pharmaceutical:Research Funding;Asahi Kasei:Research Funding;Shionogi:Research Funding;Nippon Shinyaku:Honoraria, Research Funding.Ishitsuka:Celgene:Other: Personal Fees;Kyowa Hakko Kirin:Other: Personal fees, Research Funding;BMS:Other: Personal fees;Chugai Pharmaceutical:Other: Personal fees, Research Funding;Takeda:Other: Personal fees, Research Funding;mundiharma:Other: Personal fees;Taiho Pharmaceuticals:Other: Personal fees, Research Funding;Janssen Pharmaceuticals:Other: Personal fees;Novartis:Other: Personal fees;Pfizer:Other: Personal fees;Astellas Pharma:Other, Research Funding;Genzyme:Other;Sumitomo Dainippon Pharma:Other, Research Funding;Eisai:Other, Research Funding;Mochida:Other, Research Funding;Shire:Other;Otsuka Pharmaceutical:Other;Ono Pharmaceutical:Other, Research Funding;Teijin Pharma:Research Funding;MSD:Research Funding;Asahi kasei:Research Funding;Eli Lilly:Research Funding;Daiichi Sankyo:Other;Huya Japan:Other.Minami:Bristol-Myers Squibb Company:Honoraria;Novartis Pharma KK:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda:Honoraria.
- Published
- 2020
50. Whole-Genome Analysis of Adult T-Cell Leukemia/Lymphoma
- Author
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Sumito Shingaki, Mariko Tabata, Junji Koya, Kenji Ishitsuka, Tomonori Hidaka, Yuki Saito, Takuro Kameda, Yuichi Shiraishi, Murali Janakiram, Makoto Yoshimitsu, Kisato Nosaka, R. Alejandro Sica, Aditi Shastri, Atae Utsunomiya, Ana Acuna-Villaorduna, Yasunori Kogure, Akifumi Takaori-Kondo, Keisuke Kataoka, Marni B McClure, Michihiro Hidaka, Kota Yoshifuji, Ayako Kamiunten, Yoko Kubuki, Urvi A Shah, Masao Matsuoka, Yoshitaka Imaizumi, Tatsuhiro Shibata, Juan Carlos Ramos, Mizuki Watanabe, Kazuya Shimoda, Kotaro Shide, Yasushi Miyazaki, B. Hilda Ye, and Seishi Ogawa
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medicine.medical_specialty ,Kyowa hakko ,Medical treatment ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Patient management ,Molecular classification ,Family medicine ,medicine ,Overall survival ,Stat signaling ,business - Abstract
Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy with a dismal prognosis, caused by HTLV-1. Although our previous study, mainly using whole-exome sequencing and SNP array karyotyping, discovered many driver mutations and copy number alterations (CNAs), the whole-genome landscape of ATL still remains elusive. To this end, we have performed high-depth whole-genome sequencing (WGS) of 155 ATL cases with a median sequencing depth of 96-fold for tumors. Among them, 75 cases were also analyzed by RNA sequencing (RNA-seq). In total, we detected 1,952,490 single nucleotide variants (SNVs) and 159,141 insertion-deletions (4.0 SNVs and 0.3 indels/Mb/case), 10,279 SVs (66.3 SVs/case), and 3,975 CN altered segments (25.7 segments/case). Using several driver discovery algorithms (dNdScv, MutSig2CV, and DriverPower), we identified 47 significantly mutated genes, 19 of which were mutated in more than 10% of cases. These included several novel mutations, such as those affecting XPO1 (7.1%), ZNF292 (6.5%), and ITGB1 (5.2%). Using GISTIC2.0, we identified 13 significant CNAs, such as IRF4 amplifications and CDKN2A deletions, consistent with previous SNP array data. To detect significantly recurrent SVs, we calculated SV breakpoint frequency and identified 13 genes affected by SVs, including the previously identified genes (such as CARD11, CD274, and TP73). In addition, we investigated recurrent mutations in non-coding elements by DriverPower and LARVA and discovered 12 recurrently mutated elements. Among them, the most frequent were splice site mutations, including those of HLA-A and HLA-B, most of which caused loss of function as revealed by RNA-seq. By contrast, we found recurrent mutations in TP73 splice site, which induced skipping of exons 2 and 3, generating a dominant-negative variant similar to their SVs. In addition, recurrent non-coding elements contained several novel regions, such as 3´-untranslated region (UTR) of NFKBIZ and 5´- UTR of TMSB4X. Altogether, a total of 56 genes were recurrently altered. The median number of driver alterations was eight per case, and at least one driver alteration was found in 149 cases (96.1%). Among 56 driver genes, 40 (71.4%) genes were affected by more than one alteration class. Some drivers, such as CDKN2A, IKZF2, and CD274, were affected almost exclusively by CNAs and/or SVs, while showing quite high alteration frequencies (11.6-29.0%). These observations suggest that WGS presented a substantially different overview of driver alterations from our previous study. The overall numbers of mutations and SVs were linked to these driver alterations, suggesting their etiology. In particular, inactivation of EP300 and immune-related molecules, such as HLA-A, HLA-B, and CD58, were associated with an increased number of mutations and SVs, especially deletions and tandem duplications. By contrast, cases with TP53-altered cases harbored more inversions and translocations. These results emphasize a pivotal role of immune evasion for acquiring genetic alterations to drive ATL progression. To define molecular subgroups in ATL, we integrated the 56 identified genetic drivers using non-negative matrix factorization clustering and identified two robust subgroups with discrete clinical and genetic characteristics. Group 1 was enriched with alterations affecting distal components of T-cell receptor (TCR)/NF-κB signaling (such as CARD11, PRKCB, and IRF4) and immune-related molecules (HLA-A, HLA-B, and CD58), whereas proximal regulators of TCR/NF-κB signaling (PLCG1, VAV1, and CD28) and a JAK/STAT signaling molecule (STAT3) were more frequently altered in group 2. In addition, group 1 cases had a larger number of mutations, SVs, and CNAs than group 2 cases. Clinically, most cases with lymphoma subtype were classified into group 1, whereas group 2 mainly consisted of cases with leukemic subtypes. Moreover, group1 cases showed a worse overall survival than group 2, independently of clinical subtype. These results suggest the biological and clinical relevance of the molecular classification of ATL. In summary, our WGS analysis not only identifies novel somatic alterations but also extends the overview of ATL genome. We also propose a new molecular classification of ATL, with its clinical relevance, which can lead to the future improvement of patient management. Disclosures Kogure: Takeda Pharmaceutical Company Limited.: Honoraria. Nosaka:Kyowa Kirin Co.Ltd: Honoraria; Chugai pharmaceutical Co. Ltd: Honoraria; Novartis international AG: Honoraria; Celgene K.K: Honoraria; Eisai Co., Ltd: Honoraria; Merck Sharp & Dohme K.K.: Honoraria; Bristol-Myer Squibb: Honoraria. Imaizumi:Kyowa Kirin Co. Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria. Utsunomiya:Kyowa Kirin: Honoraria; Celgene: Honoraria. Shah:Celgene: Research Funding; BMS: Research Funding; Physicians Education Resource: Honoraria. Janakiram:Takeda, Fate, Nektar: Research Funding. Ramos:NIH: Research Funding. Takaori-Kondo:Astellas Pharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; Eisai: Research Funding; Nippon Shinyaku: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria. Miyazaki:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis Pharma KK: Honoraria; Astellas Pharma Inc.: Honoraria. Matsuoka:Chugai Pharmaceutical Co. Ltd: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Kirin Co. Ltd.: Research Funding. Ishitsuka:Takeda: Other: Personal fees, Research Funding; mundiharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other, Research Funding; Genzyme: Other; Sumitomo Dainippon Pharma: Other, Research Funding; Eisai: Other, Research Funding; Mochida: Other, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other; Ono Pharmaceutical: Other, Research Funding; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Daiichi Sankyo: Other; Huya Japan: Other; Celgene: Other: Personal Fees; Kyowa Hakko Kirin: Other: Personal fees, Research Funding; BMS: Other: Personal fees; Chugai Pharmaceutical: Other: Personal fees, Research Funding. Ogawa:Asahi Genomics Co., Ltd.: Current equity holder in private company; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding. Shimoda:Takeda Pharmaceutical Company: Honoraria; Bristol-Myers Squibb: Honoraria; Shire plc: Honoraria; Celgene: Honoraria; Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding; Novartis: Honoraria, Research Funding. Kataoka:CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Genomics: Current equity holder in private company.
- Published
- 2020
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