Mogamulizumab-Associated Acute Myocarditis in a Patient With T-Cell Lymphoma.
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ABSTRACT:
SUBMITTER: Kwan JM
PROVIDER: S-EPMC8311348 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mogamulizumab is being increasingly prescribed for the treatment of T-cell lymphomas (MF/SS/ATLL). We conducted a retrospective cohort study to identify muscular immune-related adverse events (irAEs) associated with mogamulizumab in patients with T-cell lymphoma followed at Dana-Farber Cancer Institute from January 2015 to June 2022. We identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc), 2 additionally affected by myasthenia gravis, among 42 patients with T-cell lymphoma. Three cases experienced -mogamulizumab-associated rash (MAR) prior to developing MAM/Mc. The incidence (n = 5/42, 11.9%) of muscular mogamulizumab-associated irAEs may be higher than has been previously reported in clinical trials and may be of late onset (a median of 5 cycles and as late as 100 days from the last infusion). We highlight the utility of IVIG, together with systemic corticosteroids, for the treatment of these potentially fatal side effects associated with mogamulizumab therapy.
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Project description:Cutaneous T-cell lymphoma (CTCL) poses unique treatment challenges, given its range of presentations and numerous systemic therapy options. These options often lack comparative evidence or are characterized by low response rates and short remission duration in relapsed/refractory disease. The approval of mogamulizumab, a humanized, glycoengineered IgG1κ monoclonal antibody targeting the chemokine receptor type 4 (CCR4) chemokine receptor, brings a novel tool into the spectrum of treatment options for advanced CTCL and adult T-cell leukemia/lymphoma (ATLL). CCR4 is expressed in almost all cases of ATLL, and in a majority of CTCLs, particularly when blood involvement is present. In a Phase III randomized trial, mogamulizumab was associated with 28% overall response rate among patients with relapsed CTCL, median progression-free survival of 7.7 months, and median duration of remission of 14.1 months. Responses are more frequent among patients with Sézary syndrome and within the blood compartment. Common adverse effects include rash and infusion reactions, which are usually low grade. Sentinel reports indicate that exposure to mogamulizumab may result in severe or refractory graft vs host disease after allogeneic bone marrow transplantation, highlighting the need for vigilance and expert management. Further research may establish incremental efficacy of combining mogamulizumab with cytotoxic or immunomodulatory agents in CTCL, ATLL, and possibly other lymphomas and even solid tumors.
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Project description: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.
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Project description:BackgroundMogamulizumab is a humanized antibody against chemokine receptor type 4. It was recently approved by the US Food and Drug Administration for relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS). The most commonly reported adverse event in the phase III licensing trial was drug eruption (28%), now termed mogamulizumab-associated rash (MAR). Clinical recommendations about MAR and its treatment differ between the current package insert and postapproval insights reported from two single-centre studies that focused on its characterization, but less so on outcomes and clinicopathological differentiation from cutaneous T-cell lymphoma (CTCL).ObjectivesTo describe our experience in the diagnosis of MAR and treatment of patients with CTCL with mogamulizumab.MethodsThis is a single-centre retrospective case series study.ResultsWe found a higher incidence of MAR in patients with CTCL (17 of 24, 68%) than previously reported. MAR development is associated with complete (11 of 17) or partial (four of 17) responses, with an overall response rate of 88%, compared with 29% (two of seven) in patients without MAR. Diagnosis of MAR may be obscured by its ability to mimic key CTCL features both clinically and histologically, but an absence of T-cell-receptor clonality and relatively decreased CD4 : CD8 ratio compared with baseline lesions strongly favour MAR over recurrent disease.ConclusionsMAR has the potential to create a significant management problem for patients on mogamulizumab. Misidentification of MAR as recurrent CTCL may detrimentally result in the premature discontinuation of mogamulizumab in patients whose disease is historically hard to treat. Thorough clinicopathological investigation of new lesions during treatment with mogamulizumab is required to inform ideal treatment decisions and achieve better outcomes.
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Project description: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 ? 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.
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