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      Spotlight on Mogamulizumab-Kpkc for Use in Adults with Relapsed or Refractory Mycosis Fungoides or Sézary Syndrome: Efficacy, Safety, and Patient Selection

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          Abstract

          Advanced cutaneous T cell lymphomas (CTCL) including mycosis fungoides (MF) and Sézary syndrome (SS) are often difficult to manage once they become resistant to initial systemic treatment. Current systemic treatments usually provide a limited duration of disease control, leaving this an area in desperate need of new treatment options for better long-term control. These conditions often affect the older population where transplantation may not be a feasible option. Recent studies evaluated a novel CCR4 humanized monoclonal antibody, mogamulizumab, in relapsed/refractory MF and SS, which show a meaningful progression free survival (PFS) benefit. In August 2018, mogamulizumab was approved by the FDA for the treatment of patients with relapsed/refractory MF/SS who have failed at least one treatment. Approval was based on the Phase III MAVORIC study comparing mogamulizumab to vorinostat, an FDA approved drug for this indication, in 372 patients. In this trial, mogamulizumab was found to have a superior PFS with a median of 7.7 months compared to 3.1 months in the vorinostat arm, with a hazard ratio of 0.53, p<0.001. Mogamulizumab was well tolerated with the most common AE being infusion-related reactions (32%), drug rash (20%), diarrhea (23%), and fatigue (22%). We reviewed the literature leading to the development and approval of mogamulizumab and suggest which patients may benefit the most from this treatment.

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          Most cited references 18

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          Unique Chemotactic Response Profile and Specific Expression of Chemokine Receptors Ccr4 and Ccr8 by Cd4+Cd25+ Regulatory T Cells

          Chemokines dictate regional trafficking of functionally distinct T cell subsets. In rodents and humans, a unique subset of CD4+CD25+ cytotoxic T lymphocyte antigen (CTLA)-4+ regulatory T cells (Treg) has been proposed to control peripheral tolerance. However, the molecular basis of immune suppression and the trafficking properties of Treg cells are still unknown. Here, we determined the chemotactic response profile and chemokine receptor expression of human blood-borne CD4+CD25+ Treg cells. These Treg cells were found to vigorously respond to several inflammatory and lymphoid chemokines. Treg cells specifically express the chemokine receptors CCR4 and CCR8 and represent a major subset of circulating CD4+ T cells responding to the chemokines macrophage-derived chemokine (MDC)/CCL22, thymus and activation-regulated chemokine (TARC)/CCL17, I-309/CCL1, and to the virokine vMIP-I (ligands of CCR4 and CCR8). Blood-borne CD4+ T cells that migrate in response to CCL1 and CCL22 exhibit a reduced alloproliferative response, dependent on the increased frequency of Treg cells in the migrated population. Importantly, mature dendritic cells preferentially attract Treg cells among circulating CD4+ T cells, by secretion of CCR4 ligands CCL17 and CCL22. Overall, these results suggest that CCR4 and/or CCR8 may guide Treg cells to sites of antigen presentation in secondary lymphoid tissues and inflamed areas to attenuate T cell activation.
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            Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.

            KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL). Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design. Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses. KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.
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              Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors.

              Cutaneous T-cell lymphoma (CTCL) encompasses leukemic variants (L-CTCL) such as Sézary syndrome (SS) and primarily cutaneous variants such as mycosis fungoides (MF). To clarify the relationship between these clinically disparate presentations, we studied the phenotype of T cells from L-CTCL and MF. Clonal malignant T cells from the blood of L-CTCL patients universally coexpressed the lymph node homing molecules CCR7 and L-selectin as well as the differentiation marker CD27, a phenotype consistent with central memory T cells. CCR4 was also universally expressed at high levels, and there was variable expression of other skin addressins (CCR6, CCR10, and CLA). In contrast, T cells isolated from MF skin lesions lacked CCR7/L-selectin and CD27 but strongly expressed CCR4 and CLA, a phenotype suggestive of skin resident effector memory T cells. Our results suggest that SS is a malignancy of central memory T cells and MF is a malignancy of skin resident effector memory T cells.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                16 September 2020
                2020
                : 14
                : 3747-3754
                Affiliations
                [1 ]Division of Hematology/Oncology, Department of Medicine, University of California, Irvine , Irvine, CA, USA
                [2 ]Chao Family Comprehensive Cancer Center, University of California, Irvine , Irvine, CA, USA
                Author notes
                Correspondence: Lauren Pinter-Brown Email lpinterb@uci.edu
                Article
                185896
                10.2147/DDDT.S185896
                7502391
                © 2020 Blackmon and Pinter-Brown.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

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                Figures: 0, Tables: 2, References: 27, Pages: 8
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