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Madeleine Duvic - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of Mogamulizumab in previously treated patients with less advanced mycosis fungoides results from the mavoric study
    Journal of Clinical Oncology, 2019
    Co-Authors: Larisa J Geskin, Mollie Leoni, Madeleine Duvic, Martine Bagot, Julia Scarisbrick, David C Fisher, Craig A Elmets, M Beylotbarry, Junji Moriya, Pier Luigi Zinzani
    Abstract:

    e19031Background: In the MAVORIC Phase 3 study, patients (pts) with previously treated mycosis fungoides (MF)/Sezary syndrome (SS) stage IB-IVB who received Mogamulizumab (MOGA) had significantly p...

  • long term clinical benefit to anti ccr4 Mogamulizumab results from the phase 3 mavoric study in previously treated cutaneous t cell lymphoma ctcl
    Blood, 2018
    Co-Authors: Martine Bagot, Madeleine Duvic, Lubomir Sokol, Craig A Elmets, S Dalle, Athanasios Tsianakas, Amy Musiek, Pablo L Ortizromero, Brian Poligone, Mollie Leoni
    Abstract:

    Background: CTCL represents a rare group of non-Hodgkin lymphomas with substantial negative impact on patient (pt) quality of life and mortality in advanced-stage disease. Mycosis fungoides (MF), the most common subtype of CTCL, and the rarer leukemic variant Sezary syndrome (SS) are distinct subtypes of CTCL. Mogamulizumab is a first-in-class, defucosylated monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), which is highly expressed on malignant T-cells in CTCL. Primary results from the MAVORIC study (data cut-off December 2016), a phase 3 trial comparing Mogamulizumab to FDA-approved vorinostat in adults with relapsed/refractory MF/SS, showed Mogamulizumab significantly prolonged median progression-free survival compared with vorinostat (7.7 vs 3.1 months, P Methods: This was an open-label, randomized, international, phase 3 study (NCT01728805). Pts with MF/SS who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive Mogamulizumab (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral vorinostat (400 mg daily). In this follow-up analysis (data cut-off September 2017), exposure quartiles were determined, and baseline demographics, confirmed global response rate, and safety were analyzed by exposure group. To detect linear trends across exposure quartiles, frequencies were analyzed using Chi-square test and continuous data were assessed by analysis of variance. Results: A total of 184 pts randomized to Mogamulizumab were included in this analysis. Mean time of Mogamulizumab exposure was 275 days (d; standard deviation [SD]: 292 d; range: 1-1617). Based on quartile assessment, >351 d was defined as cut-off for long-term exposure. Baseline characteristics across exposure groups are shown in the Table. Significant trends were observed for baseline Eastern Cooperative Oncology Group performance status (ECOG PS; P=0.04), disease type (P=0.03), and blood involvement (defined as ≥B1 per Olsen et al J Clin Oncol 2011; P 351 d, 76% had a confirmed global response (ie, either complete or partial response). The percentage of pts reporting a treatment-emergent adverse event (AE) or serious AE did not vary with increasing exposure to Mogamulizumab ( 351 d: 21% and 4%, respectively). The most common treatment-related AEs reported by pts after >351 d of exposure to Mogamulizumab were drug eruption (9/45 [20%]), thrombocytopenia (5/45 [11%]), stomatitis (4/45 [9%]), and anemia (4/45 [9%]). Conclusions: This follow-up analysis of the phase 3 MAVORIC study demonstrated Mogamulizumab treatment of pts with MF/SS for approximately 1 year was not associated with an increased safety risk. Significant long-term clinical benefit was observed in pts with blood involvement at baseline, regardless of CCR4 expression status. A higher proportion of pts who had long-term (>351 days) exposure attained confirmed global response versus those who had less exposure. Disclosures Bagot:Takeda: Membership on an entity9s Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity9s Board of Directors or advisory committees; Actelion: Membership on an entity9s Board of Directors or advisory committees. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Tsianakas:Kyowa Kirin: Research Funding. Musiek:Seattle Genetics: Honoraria; Kyowa Kirin: Honoraria; Actelion: Other: Scientific Advisory Committee . Ortiz-Romero:Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding; Actelion: Consultancy; 4SC: Consultancy. Poligone:Johnson and Johnson: Research Funding; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding; Mallinckrodt: Speakers Bureau; Stemline Therapeutics: Honoraria; Seattle Genetics: Honoraria. Duvic:Clinical Care Options: Consultancy; Soligenix, Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Huron Consulting Group: Consultancy; Taiwan Liposome Company LTD: Consultancy; Rhizen Pharma: Research Funding; Seattle Genetics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Precision Oncology, LLC: Membership on an entity9s Board of Directors or advisory committees; Eisai: Research Funding; UT MD Anderson Cancer Center: Employment; Dr. Reddy9s Laboratories (A.K.A. Promius Pharma): Consultancy; Defined Health: Consultancy; Medivir AB: Membership on an entity9s Board of Directors or advisory committees; Medscape: Other: Speaker/Preceptor; Guidepoint Global: Consultancy; Jonathan Wood & Associates: Other: Speaker; Celgene Corp: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Evidera, Inc.: Consultancy; Kiniksa Pharmaceuticals: Consultancy; MEDACorp: Consultancy; The Lynx Group: Consultancy; Spatz Foundation: Research Funding; Forty Seven, Inc.: Membership on an entity9s Board of Directors or advisory committees; Shape: Research Funding; Aclaris Therapeutics Int9l Ltd.: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Allos: Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity9s Board of Directors or advisory committees; Concert Pharmaceuticals, Inc.: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int9l: Consultancy; Array Biopharma: Consultancy, Honoraria; Oncoceuticals: Research Funding; Tetralogics: Research Funding. Elmets:NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Association: Research Funding; Soligenix: Research Funding; Elorac: Research Funding; Leo Pharma: Other: Data and Safety Monitoring Board. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Kim:miRagen: Research Funding; Forty Seven Inc: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity9s Board of Directors or advisory committees; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees; Galderma: Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding.

  • evaluation of symptom and side effect bother in cutaneous t cell lymphoma patients treated with Mogamulizumab or vorinostat
    Blood, 2018
    Co-Authors: Stacie Hudgens, Mollie Leoni, Pierluigi Porcu, Pietro Quaglino, Auris Huen, Lysbeth Floden, Madeleine Duvic
    Abstract:

    OBJECTIVES: To determine whether individual items on patient-reported outcome measures show significant differences over the course of treatment for patients with cutaneous T-cell lymphoma (CTCL). METHODS: A large, open-label, multi-center, randomized, Phase 3 study compared Mogamulizumab, an anti-C-C chemokine receptor type 4 (CCR4)-targeted antibody, versus vorinostat in 372 CTCL patients who had failed ≥ 1 prior systemic therapy. Clinical quality of life (QoL) measurements included Skindex-29, Functional Assessment of Cancer Therapy-General (FACT-G), and two measures of pruritus (a Likert Scale and ItchyQoL). Analyses on identified individual symptom items of Skindex-29 and toxicity items of FACT-G were conducted using longitudinal generalized estimation equations (GEE) of the post-baseline, treated period assessments (through Cycles 5 or 6, depending on collection schedule) for these items. The proportion of patients experiencing a 1-grade improvement is presented in terms of frequency and percentage by treatment arm. Forest plots of odds ratios (OR) and associated confidence intervals (CI) from the GEE analyses were generated to characterize the likelihood of a 1-grade categorical improvement (eg, improvement by 1 category on the verbal response scale) on individual items for patients treated with Mogamulizumab compared to vorinostat during the first 6 cycles of therapy. RESULTS: The likelihood of patients experiencing a 1-grade improvement in skin symptoms, side effect bother, and lack of energy was higher for patients treated with Mogamulizumab compared to vorinostat (OR > 1.0). Patients treated with Mogamulizumab were more likely to observe a 1-grade improvement in painful skin (OR=1.74, CI=1.180-2.572), irritated skin (OR=1.34, CI=0.909-1.978), lack of energy (OR=2.20, CI=1.461-3.309), side effect bother (OR=1.28, CI=0.810-2.020), and general cancer pain (OR=1.38, CI=0.922-2.063) within 6 cycles of therapy (Figure). The single item descriptive and proportion analysis of 1+ grade improvement at cycle 5 from baseline is presented (Table). CONCLUSIONS: These data provide detailed information on the cumulative probability of categorical improvement of individual items on the skin symptoms of Skindex-29 and the toxicity bother, energy, and pain items of FACT-G. These results support symptom benefit of Mogamulizumab over the course of treatment compared to vorinostat. Disclosures Porcu: Innate Pharma: Consultancy. Leoni: Kyowa Kirin: Employment. Duvic: Oncoceuticals: Research Funding; Precision Oncology, LLC: Membership on an entity9s Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; UT MD Anderson Cancer Center: Employment; Aclaris Therapeutics Int9l Ltd.: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Defined Health: Consultancy; Jonathan Wood & Associates: Other: Speaker; Allos: Research Funding; Array Biopharma: Consultancy, Honoraria; Cell Medica Inc.: Consultancy, Honoraria; Concert Pharmaceuticals, Inc.: Consultancy; Guidepoint Global: Consultancy; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity9s Board of Directors or advisory committees; Shape: Research Funding; Medscape: Other: Speaker/Preceptor; Huya Bioscience Int9l: Consultancy; Eisai: Research Funding; Dr. Reddy9s Laboratories (A.K.A. Promius Pharma): Consultancy; Forty Seven, Inc.: Membership on an entity9s Board of Directors or advisory committees; Clinical Care Options: Consultancy; Huron Consulting Group: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Soligenix, Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Kiniksa Pharmaceuticals: Consultancy; The Lynx Group: Consultancy; Celgene Corp: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; MEDACorp: Consultancy; Medivir AB: Membership on an entity9s Board of Directors or advisory committees; Taiwan Liposome Company LTD: Consultancy; Evidera, Inc.: Consultancy; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Tetralogics: Research Funding; Seattle Genetics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding.

  • Mogamulizumab for the treatment of relapsed or refractory adult t cell leukemia lymphoma
    Expert Review of Hematology, 2017
    Co-Authors: Frank Winsett, Daniel J Lewis, Madeleine Duvic
    Abstract:

    ABSTRACTIntroduction: Adult T-cell leukemia-lymphoma (ATL) is an aggressive variant of peripheral T-cell lymphoma of CD4+ T-malignant cells caused by human T-lymphotropic virus type-1. Despite aggressive treatment with multidrug combination chemotherapies, ATL confers a poor prognosis and commonly develops resistance to conventional treatments.Areas covered: Mogamulizumab is a humanized, defucosylated monoclonal antibody that acts by targeting the CC chemokine receptor 4 (CCR4) on malignant cells of ATL. In phase I and II clinical trials, it has achieved overall response rates of 31–50% in CCR4+ malignancies. The most commonly observed hematologic and non-hematologic adverse events included lymphocytopenia, neutropenia, leukocytopenia, infusion reaction, rash, and pyrexia.Expert commentary: Mogamulizumab has shown significant efficacy in treating ATL with moderately high response rates and has been approved in Japan for use in ATL. It may serve as a bridge therapy to achieve disease control prior to allog...

  • Mogamulizumab in the treatment of cutaneous t cell lymphoma
    Expert opinion on orphan drugs, 2016
    Co-Authors: Frank Winsett, Xiao Ni, Madeleine Duvic
    Abstract:

    ABSTRACTIntroduction: Cutaneous T cell lymphomas are a heterogeneous group of malignancies characterized by the accumulation of malignantly transformed skin homing T cells. Mycosis fungoides, a typically indolent form of cutaneous T cell lymphoma characterized by patches, plaques, and tumors, and Sezary syndrome, a leukemic variant, make up the majority of cutaneous T cell lymphomas, and prognosis in advanced-stage disease remains poor. The defucosylated monoclonal antibody, Mogamulizumab, targets the CC chemokine receptor 4 on malignant cells of cutaneous T cell lymphoma and offers a novel approach to treating advanced-stage disease.Areas covered: Mogamulizumab has shown efficacy in phase I/II clinical trials in patients with cutaneous T cell lymphoma, with overall response rates between 35–36.8%. Currently, a phase III trial is underway comparing Mogamulizumab to vorinostat in the treatment of cutaneous T cell lymphoma.Expert opinion: Mogamulizumab has already been approved in Japan for the treatment of...

Takashi Ishida - One of the best experts on this subject based on the ideXlab platform.

  • Mogamulizumab for relapsed adult t cell leukemia lymphoma updated follow up analysis of phase i and ii studies
    Cancer Science, 2017
    Co-Authors: Takashi Ishida, Kazuhito Yamamoto, Atae Utsunomiya, Koji Kato, Tatsuro Jo, Shigeki Takemoto, Hitoshi Suzushima, Shinichiro Yoshida, Yukio Kobayashi, Yoshitaka Imaizumi
    Abstract:

    Summary The present study sought to elucidate the prognosis of adult T-cell leukemia–lymphoma (ATL) patients receiving Mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are updated here, namely NCT00355472 (phase I study of Mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived > 3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, while median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed only a grade 1 rash, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥ grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that Mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of Mogamulizumab. This article is protected by copyright. All rights reserved.

  • monitoring of adult t cell leukemia lymphoma cells in patients receiving Mogamulizumab a humanized anti ccr4 monoclonal antibody using t cell receptor repertoire analysis
    Blood, 2016
    Co-Authors: Masato Saito, Shigeru Kusumoto, Takashi Ishida, Hiroshi Inagaki, Toshihiko Ishii, Itaru Urakawa, Ayako Masaki, Susumu Suzuki, Hirokazu Komatsu, Takeshi Takahashi
    Abstract:

    Introduction Adult T-cell leukemia-lymphoma (ATL), a rare peripheral T-cell lymphoma, is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Mogamulizumab-a humanized anti-CCR4 monoclonal antibody-shows antitumor activities in patients with ATL, and was approved in Japan for the treatment of CCR4+ relapsed/refractory ATL, followed by treatment of CCR4+ untreated ATL under the combination with chemotherapies. However, relapse may still be a problem in some patients with ATL, even in those who achieve complete hematological remission after Mogamulizumab treatment. Therefore, highly accurate monitoring of ATL cells could be useful for elucidating the mechanisms of hematological relapse. Detecting ATL cells among peripheral blood mononuclear cells (PBMCs) has been performed clinically by measuring abnormal lymphocytes, HTLV-1 provirus DNA using PCR, and analyzing surface markers using flow cytometry. These, however, cannot reveal the entire picture of heterogeneous ATL cell populations. Because ATL is a malignant form of differentiated T cell and expresses a specific T-cell receptor (TCR), we conducted a TCR repertoire analysis of peripheral blood to elucidate the complete ATL clonotype using next generation sequencing (NGS). Methods PBMCs were obtained sequentially at pre-, during-, and post-treatment from patients with ATL who received Mogamulizumab (n = 11). Total RNA was extracted from these PBMCs, and TCR alpha- and beta-chain variable regions were amplified by the SMARTer 59RACE method using a 39 primer positioned in the constant region. The amplified variable regions were sequenced using Ion PGM sequencer (Thermo Fisher Scientific). Germline usage [Variable (V), Diversity (D), and Joining (J) gene segments] of each sequence was identified using IgBlast (NCBI) and frequency of each germline was calculated. The major germline gene segments in the pre-treatment samples, which are presumed to be ATL clones, were monitored during treatment and their frequency changes were analyzed. Results Tens of thousands sequence reads of the TCR variable region were obtained from each sample. In most cases, the majority of PBMCs at pre-treatment were considered to be ATL cells as evidenced by the HTLV-1 virus load. Therefore, the highly frequent TCR germline gene segments detected in the pre-treatment samples were thought to be derived from ATL cells. Such gene segments were significantly decreased in the post-Mogamulizumab treatment samples (Table 1). In a patient who received Mogamulizumab, the frequencies of the most abundant TCRa and TCRb clones were 66.8% and 32.8%, respectively, before treatment and decreased to 0.00617% and an undetectable level, 109 days after initial treatment-66 days after discontinuation of treatment, along with HTLV-1 virus load decrease. In this patient, the same clones increased again to 66.5% and 7.54%, respectively, along with HTLV-1 virus load increase, 342 days after initial treatment-299 days after discontinuation. Increase of the clones was detected as early as 167 days after initial treatment-124 days after discontinuation. In 4 of 11 patients with ATL who received Mogamulizumab, a resurgence of clones that were dominant at pre-treatment was detected. These recurrent clones were thought to express CCR4-measured by quantitative PCR in PBMCs-because the change in CCR4 gene expression levels during treatment were correlated with the changes in HTLV-1 virus load, frequency of dominant clones, and expression of the HBZ gene, which is transcribed from the HTLV-1 genome. Discussion and Conclusions The TCR repertoire analysis using NGS made it possible to track specific ATL clones during Mogamulizumab treatment. We observed that most ATL clones were drastically depleted after Mogamulizumab treatment. However, in some patients, regrowth of ATL cells in blood was observed. By the TCR repertoire analysis, it was indicated that these regrown ATL clones were derived from the same ones that were dominant at pre-treatment. Moreover, these clones were thought to express CCR4. Thus, TCR repertoire analysis using NGS may be useful for elucidating the mechanisms of hematological relapse after Mogamulizumab treatment, as well as early detection of hematological relapse. Disclosures Saito:Kyowa Hakko Kirin Co., Ltd.: Employment. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Urakawa:Kyowa Hakko Kirin Co., Ltd.: Employment. Ishii:Kyowa Hakko Kirin Co., Ltd.: Employment. Suzuki:Kyowa Hakko Kirin: Research Funding. Inagaki:Kyowa Hakko Kirin: Research Funding. Takahashi:Kyowa Hakko Kirin Co., Ltd.: Employment. Ueda:Kyowa Hakko Kirin: Research Funding; Mundipharma KK: Consultancy. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.

  • fatal reactivation of hepatitis b virus infection in a patient with adult t cell leukemia lymphoma receiving the anti cc chemokine receptor 4 antibody Mogamulizumab
    Hepatology Research, 2015
    Co-Authors: Hideki Ifuku, Shigeru Kusumoto, Takashi Ishida, Ryuzo Ueda, Yasuhito Tanaka, Masashi Mizokami, Haruhito Totani, Masaya Okada, Shuko Murakami, Shinsuke Iida
    Abstract:

    We report an adult T-cell leukemia–lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, Mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, Mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

  • dose intensified chemotherapy alone or in combination with Mogamulizumab in newly diagnosed aggressive adult t cell leukaemia lymphoma a randomized phase ii study
    British Journal of Haematology, 2015
    Co-Authors: Takashi Ishida, Kazuhito Yamamoto, Naokuni Uike, Tatsuro Jo, Shigeki Takemoto, Hitoshi Suzushima, Kimiharu Uozumi, Yoshio Saburi, Kisato Nosaka, Atae Utsunomiya
    Abstract:

    This multicentre, randomized, phase II study was conducted to examine whether the addition of Mogamulizumab, a humanized anti‐CC chemokine receptor 4 antibody, to mLSG15, a dose‐intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus Mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15‐plus‐Mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33–71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16–55%) and 75%, respectively. Grade ≥ 3 treatment‐emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15‐plus‐Mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15‐plus‐Mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: {"type":"clinical-trial","attrs":{"text":"NCT01173887","term_id":"NCT01173887"}}NCT01173887.

  • Fatal reactivation of hepatitis B virus infection in a patient with adult T-cell leukemia–lymphoma receiving the anti-CC chemokine receptor 4 antibody Mogamulizumab
    Hepatology Research, 2015
    Co-Authors: Hideki Ifuku, Shigeru Kusumoto, Takashi Ishida, Ryuzo Ueda, Yasuhito Tanaka, Masashi Mizokami, Haruhito Totani, Masaya Okada, Shuko Murakami, Shinsuke Iida
    Abstract:

    We report an adult T-cell leukemia-lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, Mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, Mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

Ryuzo Ueda - One of the best experts on this subject based on the ideXlab platform.

  • fatal reactivation of hepatitis b virus infection in a patient with adult t cell leukemia lymphoma receiving the anti cc chemokine receptor 4 antibody Mogamulizumab
    Hepatology Research, 2015
    Co-Authors: Hideki Ifuku, Shigeru Kusumoto, Takashi Ishida, Ryuzo Ueda, Yasuhito Tanaka, Masashi Mizokami, Haruhito Totani, Masaya Okada, Shuko Murakami, Shinsuke Iida
    Abstract:

    We report an adult T-cell leukemia–lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, Mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, Mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

  • Fatal reactivation of hepatitis B virus infection in a patient with adult T-cell leukemia–lymphoma receiving the anti-CC chemokine receptor 4 antibody Mogamulizumab
    Hepatology Research, 2015
    Co-Authors: Hideki Ifuku, Shigeru Kusumoto, Takashi Ishida, Ryuzo Ueda, Yasuhito Tanaka, Masashi Mizokami, Haruhito Totani, Masaya Okada, Shuko Murakami, Shinsuke Iida
    Abstract:

    We report an adult T-cell leukemia-lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, Mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, Mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

  • Clinical Application of Anti-CCR4 Monoclonal Antibody
    Oncology, 2015
    Co-Authors: Ryuzo Ueda
    Abstract:

    © 2015 S. Karger AG, Basel. Mogamulizumab (KW-0761) is a humanized anti-CCR4 monoclonal antibody with a defucosylated Fc region (Potelligent® Technology), which markedly enhances antibody-dependent cellular cytotoxicity by increasing its binding affinity to the Fcx03B3; receptor expressed on effector cells. It is an effective agent for patients with CCR4-positive adult T-cell leukemia and peripheral T-cell lymphoma, for which no standard therapy exists, and it has an acceptable toxicity profile. In addition, because CCR4 is expressed on CD45RA-FOXP3highCD4+ effector regulatory T (Treg) cells, it is an even more attractive target, because Treg cells involved in the tumor escape from host immunity in the tumor microenvironment. Based on this concept, we conducted a clinical study of Mogamulizumab for the treatment of CCR4-negative advanced or recurrent solid cancer, with the aim of depleting effector Treg cells and thus boosting anti-cancer immune responses. In this study, Mogamulizumab infusion at doses ranging from 0.1 to 1.0 mg/kg was safe and well tolerated. Four of 10 patients showed stable disease during treatment and showed long-term survival. Mogamulizumab efficiently depleted effector Treg cells even at the lowest dose of 0.1 mg/kg, and an augmentation or induction of specific immune responses to cancer/testis antigens was observed in some patients. In the near future, a novel immunotherapy targeting Treg cells with Mogamulizumab will be offered to patients with different types of cancer.

  • development of Mogamulizumab and establishment of an optimal therapy based on genomic biomarkers from the academic viewpoint
    Yakugaku Zasshi-journal of The Pharmaceutical Society of Japan, 2015
    Co-Authors: Shinsuke Iida, Takashi Ishida, Ryuzo Ueda
    Abstract:

    : Mogamulizumab (Moga; KW-0761) is a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody engineered to exert potent antibody-dependent cellular cytotoxicity (ADCC). A collaborative investigation with industry in preclinical studies has demonstrated in vitro and in vivo efficacy via ADCC for adult T-cell leukemia/lymphoma (ATLL) and CCR4-positive peripheral T-cell lymphoma (PTCL). In a phase I study, once-weekly administration of Mogamulizumab (0.01-1.0 mg/kg) for 4 weeks was well tolerated. In a phase II study of once-weekly Mogamulizumab (1.0 mg/kg) for 8 weeks in relapsed/refractory ATLL patients, an overall response rate of 50% including 30% complete response rate with a median progression-free survival of 5.2 months was observed. The drug was subsequently approved by Pharmaceuticals and Medical Devices Agency(PMDA) in March 2012. Because CCR4 is abundantly expressed on the surface of effector regulatory T cells, a phase I study is being conducted to enhance antitumor immune response in patients with solid tumors. However, approximately 60% of patients receiving Mogamulizumab experience skin eruption with 19% showing grade ≥ 3 rash. Postmarketing surveillance of Mogamulizumab revealed a 3-4% incidence rate of skin-related serious adverse events (SAEs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Therefore we initiated a search for predictive genomic biomarkers in the blood of patients with ATLL or solid tumors prior to treatment with Mogamulizumab for not only efficacy but also immune-related SAEs. We believe the results of this study may lead to safer and more efficient use of this agent in the near future.

  • stevens johnson syndrome associated with Mogamulizumab treatment of adult t cell leukemia lymphoma
    Cancer Science, 2013
    Co-Authors: Takashi Ishida, Akimichi Morita, Shigeru Kusumoto, Shiro Akinaga, Shinsuke Iida, Hiroshi Inagaki, Fumihiko Sato, Ryuzo Ueda
    Abstract:

    We report an adult T-cell leukemia/lymphoma patient suffering from Stevens–Johnson Syndrome (SJS) during Mogamulizumab (humanized anti-CCR4 monoclonal antibody) treatment. There was a durable significant reduction of the CD4+CD25highFOXP3+ regulatory T (Treg) cell subset in the patient's PBMC, and the affected inflamed skin almost completely lacked FOXP3-positive cells. This implies an association between reduction of the Treg subset by mogamulizimab and occurrence of SJS. The present case should contribute not only to our understanding of human pathology resulting from therapeutic depletion of Treg cells, but also alert us to the possibility of immune-related severe adverse events such as SJS when using Mogamulizumab. We are currently conducting a clinical trial of Mogamulizumab for CCR4-negative solid cancers (UMIN000010050), specifically aiming to deplete Treg cells.

Kensei Tobinai - One of the best experts on this subject based on the ideXlab platform.

  • safety and effectiveness of Mogamulizumab in relapsed or refractory adult t cell leukemia lymphoma
    European Journal of Haematology, 2019
    Co-Authors: Kenji Ishitsuka, Takeshi Takahashi, Satoshi Yurimoto, Yukie Tsuji, Manabu Iwabuchi, Kensei Tobinai
    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.

  • Mogamulizumab for the treatment of t cell lymphoma
    Expert Opinion on Biological Therapy, 2017
    Co-Authors: Shinichi Makita, Kensei Tobinai
    Abstract:

    ABSTRACTIntroduction: T-cell lymphoma is a relatively rare hematologic malignancy that accounts for 10–20% of non-Hodgkin lymphomas. Treatment strategies for T-cell lymphomas are different from that for B-cell lymphomas and have poor prognoses. Among various subtypes of T-cell lymphomas, adult T-cell leukemia-lymphoma (ATL) has the worst prognosis. To achieve further improvement in the treatment outcome of T-cell lymphomas, several novel agents such as brentuximab vedotin, lenalidomide, romidepsin, and pralatrexate are actively being studied. Mogamulizumab, an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, is one of the promising agents for CCR4-positive T-cell lymphomas, especially for ATL.Areas covered: First, basic information about the current treatment strategy of T-cell lymphomas including ATL is described. Then, the authors discuss the current clinical development of Mogamulizumab and its clinical implications for T-cell lymphomas.Expert opinion: Mogamulizumab has potent clinical efficacy...

  • safety and efficacy of Mogamulizumab in patients with adult t cell leukemia lymphoma in japan interim results of postmarketing all case surveillance
    International Journal of Hematology, 2017
    Co-Authors: Kenji Ishitsuka, Satoshi Yurimoto, Kouichi Kawamura, Yukie Tsuji, Manabu Iwabuchi, Tsutomu Takahashi, Kensei Tobinai
    Abstract:

    We present the interim results of a postmarketing all-case surveillance study in patients with C–C chemokine receptor 4 (CCR4)-positive, relapsed or refractory adult T-cell leukemia–lymphoma (ATL) treated with the anti-CCR4 monoclonal antibody Mogamulizumab since its 2012 launch in Japan. The safety and efficacy analysis populations comprised 484 and 442 patients, respectively. The ATL subtype was acute in 58.9% and lymphoma in 34.2% of patients. All patients were scheduled to receive intravenous infusions of Mogamulizumab (1.0 mg/kg) once weekly for eight weeks, alone or in combination with other modalities. Adverse drug reactions (ADRs) were reported in 74.0% of patients, of which 35.7% were serious and 6.2% were fatal. The priority survey items of infusion-related reaction, skin disorder, infection, immune disorder, and tumor lysis syndrome were reported in 29.3, 34.3, 22.1, 3.5, and 2.5% of patients, respectively. Graft-versus-host disease was reported in 25/42 patients who received Mogamulizumab before allogeneic hematopoietic stem cell transplantation. The best overall response rate was 57.7% overall, 57.5% in patients treated with Mogamulizumab alone, and 58.2% in patients treated with combination therapy. This surveillance indicates that Mogamulizumab shows acceptable tolerability in practice; however, because of the risk of serious/fatal ADRs, patients administered Mogamulizumab should be carefully monitored.

  • An evaluation of Mogamulizumab for the treatment of peripheral T-cell lymphoma
    Expert opinion on orphan drugs, 2014
    Co-Authors: Wataru Munakata, Kensei Tobinai
    Abstract:

    Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoid malignancies that remains extremely difficult to cure and has a poor prognosis with conventional chemotherapy; therefore, novel treatment modalities are needed. CC chemokine receptor 4 (CCR4) is expressed on the tumor cells of PTCL including adult T-cell leukemia-lymphoma (ATL) and is considered to be a promising therapeutic target. Mogamulizumab, a defucosylated, humanized anti-CCR4 mAb, is produced using a novel glycoengineering technology that enhances antibody-dependent cell-mediated cytotoxic activity.Areas covered: The basic aspects and current treatment strategies against PTCL including ATL were briefly reviewed, followed by a discussion on the development of Mogamulizumab and clinical trials of this targeting agent for PTCL including ATL.Expert opinion: Mogamulizumab is the first therapeutic agent to target CCR4. Mogamulizumab monotherapy achieved a high response rate in patients with relapsed or refractory ATL an...

  • multicenter phase ii study of Mogamulizumab kw 0761 a defucosylated anti cc chemokine receptor 4 antibody in patients with relapsed peripheral t cell lymphoma and cutaneous t cell lymphoma
    Journal of Clinical Oncology, 2014
    Co-Authors: Michinori Ogura, Takashi Ishida, Kiyoshi Ando, Katsuya Fujimoto, Kazuhito Yamamoto, Kiyohiko Hatake, Toshihiro Miyamoto, Masafumi Taniwaki, Kensei Tobinai, Naokuni Uike
    Abstract:

    Purpose CC chemokine receptor 4 (CCR4) is expressed by peripheral T-cell lymphomas (PTCLs) and is associated with poor outcomes. Mogamulizumab (KW-0761) is a defucosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity. This multicenter phase II study evaluated the efficacy and safety of Mogamulizumab in patients with relapsed PTCL and cutaneous T-cell lymphoma (CTCL). Patients and Methods Mogamulizumab (1.0 mg/kg) was administered intravenously once per week for 8 weeks to patients with relapsed CCR4-positive PTCL or CTCL. The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Results A total of 38 patients were enrolled, and 37 patients received Mogamulizumab. Objective responses were noted for 13 of 37 patients (35%; 95% CI, 20% to 53%), including five patients (14%) with complete response. The median PFS was 3.0 months (95% CI, 1.6 to 4.9 months), an...

Shigeru Kusumoto - One of the best experts on this subject based on the ideXlab platform.

  • robust cd8 t cell proliferation and diversification after Mogamulizumab in patients with adult t cell leukemia lymphoma
    Blood Advances, 2020
    Co-Authors: Masato Saito, Akimichi Morita, Shigeru Kusumoto, Toshihiko Ishii, Itaru Urakawa, Asuka Matsumoto, Ayako Masaki, Susumu Suzuki, Takeshi Takahashi, Hiroshi Inagaki
    Abstract:

    : Skin-related adverse events (AEs) occur frequently in adult T-cell leukemia-lymphoma (ATL) patients treated with Mogamulizumab, a humanized anti-CCR4 monoclonal antibody. This study was undertaken to elucidate the mechanisms of Mogamulizumab-induced skin-related AEs. We analyzed the T-cell receptor β chain repertoire in ATL patients' peripheral blood mononuclear cells (PBMCs) before and after Mogamulizumab. Skin-related AEs were present in 16 patients and were absent in 8 patients. Additionally, we included 11 patients before and after chemotherapy without Mogamulizumab. Immune-related gene expression in PBMCs before and after Mogamulizumab was also assessed (n = 24). Mogamulizumab treatment resulted in CCR4+ T-cell depletion, and the consequent lymphopenia provoked homeostatic CD8+ T-cell proliferation, as evidenced by increased expressions of CD8B and CD8A, which were significantly greater in patients with skin-related AEs than in those without them. We hypothesize that proliferation is driven by the engagement of self-antigens, including skin-related antigens, in the face of regulatory T-cell depletion. Together with the observed activated antigen presentation function, this resulted in T-cell diversification that was significantly greater in patients with skin-related AEs than in those without. We found that the CD8+ T cells that proliferated and diversified after Mogamulizumab treatment were almost entirely newly emerged clones. There was an inverse relationship between the degree of CCR4+ T-cell depletion and increased CD8+ T-cell proliferation and diversification. Thus, lymphocyte-depleting Mogamulizumab treatment provokes homeostatic CD8+ T-cell proliferation predominantly of newly emerging clones, some of which could have important roles in the pathogenesis of Mogamulizumab-induced skin-related AEs.

  • Mogamulizumab treatment elicits autoantibodies attacking the skin in patients with adult t cell leukemia lymphoma
    Clinical Cancer Research, 2019
    Co-Authors: Yui Suzuki, Shigeru Kusumoto, Masato Saito, Toshihiko Ishii, Itaru Urakawa, Asuka Matsumoto, Ayako Masaki, Susumu Suzuki, Masanori Hiura
    Abstract:

    Purpose: The anti-CCR4 mAb, Mogamulizumab, offers therapeutic benefit to patients with adult T-cell leukemia-lymphoma (ATL), but skin-related adverse events (AE) such as erythema multiforme occur frequently. The purpose of this study was to determine the mechanisms by which Mogamulizumab causes skin-related AEs in patients with ATL. Experimental Design: We investigated whether autoantibodies were present in patients’ sera using flow cytometry to determine binding to keratinocytes and melanocytes (n = 17), and immunofluorescence analysis of tissue sections. We analyzed the IgM heavy chain repertoire in peripheral blood mononuclear cells before and after Mogamulizumab or other chemotherapy by next-generation sequencing (NGS; n = 16). Results: Autoantibodies recognizing human keratinocytes or melanocytes were found in the sera of 6 of 8 patients suffering from Mogamulizumab-induced erythema multiforme. In one patient, complement-dependent cytotoxicity (CDC) mediated by autoantibodies against keratinocytes or melanocytes was proportionally related to the severity of the erythema multiforme. The presence of autoantibodies in the epidermis was confirmed in all biopsy specimens of Mogamulizumab-induced erythema multiforme (n = 12). Furthermore, colocalization of autoantibodies and C1q, suggesting the activation of CDC, was observed in 67% (8/12). In contrast, no autoantibody or C1q was found in ATL tumor skin lesions (n = 13). Consistent with these findings, NGS demonstrated that IgM germline genes had newly emerged and expanded, resulting in IgM repertoire skewing at the time of erythema multiforme. Conclusions: Mogamulizumab elicits autoantibodies playing an important role in skin-related AEs, possibly associated with regulatory T-cell depletion. This is the first report demonstrating the presence of skin-directed autoantibodies after Mogamulizumab treatment.

  • monitoring of adult t cell leukemia lymphoma cells in patients receiving Mogamulizumab a humanized anti ccr4 monoclonal antibody using t cell receptor repertoire analysis
    Blood, 2016
    Co-Authors: Masato Saito, Shigeru Kusumoto, Takashi Ishida, Hiroshi Inagaki, Toshihiko Ishii, Itaru Urakawa, Ayako Masaki, Susumu Suzuki, Hirokazu Komatsu, Takeshi Takahashi
    Abstract:

    Introduction Adult T-cell leukemia-lymphoma (ATL), a rare peripheral T-cell lymphoma, is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Mogamulizumab-a humanized anti-CCR4 monoclonal antibody-shows antitumor activities in patients with ATL, and was approved in Japan for the treatment of CCR4+ relapsed/refractory ATL, followed by treatment of CCR4+ untreated ATL under the combination with chemotherapies. However, relapse may still be a problem in some patients with ATL, even in those who achieve complete hematological remission after Mogamulizumab treatment. Therefore, highly accurate monitoring of ATL cells could be useful for elucidating the mechanisms of hematological relapse. Detecting ATL cells among peripheral blood mononuclear cells (PBMCs) has been performed clinically by measuring abnormal lymphocytes, HTLV-1 provirus DNA using PCR, and analyzing surface markers using flow cytometry. These, however, cannot reveal the entire picture of heterogeneous ATL cell populations. Because ATL is a malignant form of differentiated T cell and expresses a specific T-cell receptor (TCR), we conducted a TCR repertoire analysis of peripheral blood to elucidate the complete ATL clonotype using next generation sequencing (NGS). Methods PBMCs were obtained sequentially at pre-, during-, and post-treatment from patients with ATL who received Mogamulizumab (n = 11). Total RNA was extracted from these PBMCs, and TCR alpha- and beta-chain variable regions were amplified by the SMARTer 59RACE method using a 39 primer positioned in the constant region. The amplified variable regions were sequenced using Ion PGM sequencer (Thermo Fisher Scientific). Germline usage [Variable (V), Diversity (D), and Joining (J) gene segments] of each sequence was identified using IgBlast (NCBI) and frequency of each germline was calculated. The major germline gene segments in the pre-treatment samples, which are presumed to be ATL clones, were monitored during treatment and their frequency changes were analyzed. Results Tens of thousands sequence reads of the TCR variable region were obtained from each sample. In most cases, the majority of PBMCs at pre-treatment were considered to be ATL cells as evidenced by the HTLV-1 virus load. Therefore, the highly frequent TCR germline gene segments detected in the pre-treatment samples were thought to be derived from ATL cells. Such gene segments were significantly decreased in the post-Mogamulizumab treatment samples (Table 1). In a patient who received Mogamulizumab, the frequencies of the most abundant TCRa and TCRb clones were 66.8% and 32.8%, respectively, before treatment and decreased to 0.00617% and an undetectable level, 109 days after initial treatment-66 days after discontinuation of treatment, along with HTLV-1 virus load decrease. In this patient, the same clones increased again to 66.5% and 7.54%, respectively, along with HTLV-1 virus load increase, 342 days after initial treatment-299 days after discontinuation. Increase of the clones was detected as early as 167 days after initial treatment-124 days after discontinuation. In 4 of 11 patients with ATL who received Mogamulizumab, a resurgence of clones that were dominant at pre-treatment was detected. These recurrent clones were thought to express CCR4-measured by quantitative PCR in PBMCs-because the change in CCR4 gene expression levels during treatment were correlated with the changes in HTLV-1 virus load, frequency of dominant clones, and expression of the HBZ gene, which is transcribed from the HTLV-1 genome. Discussion and Conclusions The TCR repertoire analysis using NGS made it possible to track specific ATL clones during Mogamulizumab treatment. We observed that most ATL clones were drastically depleted after Mogamulizumab treatment. However, in some patients, regrowth of ATL cells in blood was observed. By the TCR repertoire analysis, it was indicated that these regrown ATL clones were derived from the same ones that were dominant at pre-treatment. Moreover, these clones were thought to express CCR4. Thus, TCR repertoire analysis using NGS may be useful for elucidating the mechanisms of hematological relapse after Mogamulizumab treatment, as well as early detection of hematological relapse. Disclosures Saito:Kyowa Hakko Kirin Co., Ltd.: Employment. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Urakawa:Kyowa Hakko Kirin Co., Ltd.: Employment. Ishii:Kyowa Hakko Kirin Co., Ltd.: Employment. Suzuki:Kyowa Hakko Kirin: Research Funding. Inagaki:Kyowa Hakko Kirin: Research Funding. Takahashi:Kyowa Hakko Kirin Co., Ltd.: Employment. Ueda:Kyowa Hakko Kirin: Research Funding; Mundipharma KK: Consultancy. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.

  • fatal reactivation of hepatitis b virus infection in a patient with adult t cell leukemia lymphoma receiving the anti cc chemokine receptor 4 antibody Mogamulizumab
    Hepatology Research, 2015
    Co-Authors: Hideki Ifuku, Shigeru Kusumoto, Takashi Ishida, Ryuzo Ueda, Yasuhito Tanaka, Masashi Mizokami, Haruhito Totani, Masaya Okada, Shuko Murakami, Shinsuke Iida
    Abstract:

    We report an adult T-cell leukemia–lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, Mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, Mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

  • Fatal reactivation of hepatitis B virus infection in a patient with adult T-cell leukemia–lymphoma receiving the anti-CC chemokine receptor 4 antibody Mogamulizumab
    Hepatology Research, 2015
    Co-Authors: Hideki Ifuku, Shigeru Kusumoto, Takashi Ishida, Ryuzo Ueda, Yasuhito Tanaka, Masashi Mizokami, Haruhito Totani, Masaya Okada, Shuko Murakami, Shinsuke Iida
    Abstract:

    We report an adult T-cell leukemia-lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, Mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, Mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.