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[Rinsho Ketsueki] the Japanese Journal... 2023Adult T-cell leukemia/lymphoma (ATL) is an extremely refractory peripheral T-cell lymphoma that develops after persistent human T-lymphotropic virus type 1 (HTLV-1)...
Adult T-cell leukemia/lymphoma (ATL) is an extremely refractory peripheral T-cell lymphoma that develops after persistent human T-lymphotropic virus type 1 (HTLV-1) infection. In recent years, the number of HTLV-1 carriers has decreased due to lifestyle changes and different measures. Rapid progression in comprehensive genetic analysis techniques has revealed the molecular basis of ATL. Therefore, in addition to conventional prognostic indices based on clinical parameters, prognostic indices incorporating genetic mutations have been proposed. The standard treatment for untreated aggressive ATL is combination chemotherapy such as VCAP-AMP-VECP or CHOP, followed by allogeneic hematopoietic stem cell transplantation, as appropriate. Combined mogamulizumab and chemotherapy is a promising first-line treatment option for patients not eligible for transplantation. Salvage treatment with lenalidomide, brentuximab vedotin, tucidinostat, and valemetostat, in addition to mogamulizumab, has been introduced over the last decade. Advancements in allogeneic transplantation therapy, including early induction and transplantation with post-transplant cyclophosphamide for GVHD prophylaxis, have also improved patient outcomes. This article highlights recent developments in the field of ATL.
Topics: Adult; Humans; Leukemia-Lymphoma, Adult T-Cell; Human T-lymphotropic virus 1; Prognosis; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Lymphoma
PubMed: 37899180
DOI: 10.11406/rinketsu.64.1032 -
Biomolecules Oct 2023Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and... (Review)
Review
Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5-10% of carriers lose this balance and develop ATL. Coinfection with promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of HTLV-1 pathogenicity. As CD4+ T cells play a central role in host immunity, the deregulation of their function and differentiation via HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs the immunological balance. Various approaches are available for treating these abnormalities; however, hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL. The patient's immune state may contribute to the treatment outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, depends on immune function, including antibody-dependent cytotoxicity. In this comprehensive review, we summarize the immunopathogenesis of HTLV-1 infection in ATL and discuss the clinical findings that should be considered when developing treatment strategies for ATL.
Topics: Adult; Humans; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; CD4-Positive T-Lymphocytes; Lymphoma
PubMed: 37892225
DOI: 10.3390/biom13101543 -
Long-term safety and efficacy of mogamulizumab (anti-CCR4) for treating virus-associated myelopathy.Brain : a Journal of Neurology Aug 2023Some carriers of human T-cell leukaemia virus type 1 (HTLV-1), a retrovirus that primarily infects CD4+ T cells and causes lifelong infection, develop HTLV-1-associated...
Some carriers of human T-cell leukaemia virus type 1 (HTLV-1), a retrovirus that primarily infects CD4+ T cells and causes lifelong infection, develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Current treatments for HAM/TSP are insufficient with problematic long-term side effects. This study evaluated the long-term safety and efficacy of the anti-CCR4 antibody mogamulizumab in patients with HAM/TSP over a 4-year period. We conducted an open-label, extended long-term study (UMIN trial number: UMIN000019942) of a phase 1-2a trial with mogamulizumab for HAM/TSP (UMIN000012655). The study participants were patients with corticosteroid-resistant HAM/TSP who could walk 10 m with or without assistive tools. Mogamulizumab was administered at 0.01, 0.03, 0.1 or 0.3 mg/kg at intervals of ≥8 weeks (0.01 and 0.03 mg/kg) or ≥12 weeks (0.1 and 0.3 mg/kg). HTLV-1 proviral load, CSF inflammatory markers and clinical symptoms were summarized by descriptive statistics. Missing observations were imputed using the last-observation-carried-forward method. As a post hoc analysis, we evaluated the therapeutic effect of mogamulizumab on gait function by comparing it with contemporary control data from a HAM/TSP patient registry. Of the 21 participants in the phase 1-2a, 18 (86%) enrolled in the long-term study and 15 (71%) continued repeated doses of mogamulizumab for 4 years. The median dose was 0.1 mg/kg after 4 years. Seventeen of 21 participants (81%) experienced grade 1-2 skin-related adverse events. Observed grade 3 drug-related adverse effects included three cases of lymphopenia and one case each of microscopic polyangiitis, elevated levels of aspartate aminotransferase, and neutropenia. Four of 21 participants (19%) developed neutralizing antibodies. After 4 years, the peripheral blood proviral load and the number of infected cells in CSF decreased by 60.7% and 66.3%, respectively. Neopterin and CXCL10 CSF concentrations decreased by 37.0% and 31.0%, respectively. Among the 18 participants, spasticity and Osame Motor Disability Score (OMDS) improved in 17 (94%) and four (22%), respectively. However, 10 m walking time worsened by 7.3% on average. Comparison with the contemporary control group demonstrated that mogamulizumab inhibited OMDS progression (P = 0.02). The results of the study suggest that mogamulizumab has long-term safety and inhibitory effects on lower limb motor disability progression in corticosteroid-treated patients with HAM/TSP. This will provide a basis for the application of mogamulizumab in HAM/TSP treatment.
Topics: Humans; Disabled Persons; Motor Disorders; Paraparesis, Tropical Spastic; Human T-lymphotropic virus 1
PubMed: 37093965
DOI: 10.1093/brain/awad139 -
Journal of Clinical and Experimental... 2021Adult T-cell leukemia/lymphoma (ATLL) is a malignancy caused by the human T-cell leukemia virus type 1. Aggressive ATLL is refractory to conventional chemotherapy and... (Review)
Review
Adult T-cell leukemia/lymphoma (ATLL) is a malignancy caused by the human T-cell leukemia virus type 1. Aggressive ATLL is refractory to conventional chemotherapy and has a poor prognosis. Better therapeutic approaches, including cancer immunotherapy, are required to improve survival and prognosis. The genetic landscape of ATLL reveals frequent genetic alterations in genes associated with immune surveillance, including major histocompatibility complex (MHC) class I, CD58 antigen, and programmed cell death ligand 1. Clinicopathological investigations also revealed tumor immunity mechanisms in ATLL, including immune checkpoint molecules, MHC molecules, tumor-associated macrophages, and chemokines. However, the tumor microenvironment of ATLL remains complex because ATLL itself originates from T-cells, usually expressing regulatory T-cell markers. In this review, we discuss the recent literature describing the tumor microenvironment of ATLL.
Topics: Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphoma; Prognosis; Tumor Microenvironment
PubMed: 34937829
DOI: 10.3960/jslrt.21007 -
Journal of Clinical Virology : the... Oct 2023HTLV-1 infection is a neglected disease, despite producing neurological and lymphoproliferative severe illnesses and affect over 10 million people worldwide. Roughly 5%...
BACKGROUND
HTLV-1 infection is a neglected disease, despite producing neurological and lymphoproliferative severe illnesses and affect over 10 million people worldwide. Roughly 5% of HTLV-1 carriers develop Adult T-cell leukemia/lymphoma (ATLL), one of the most aggressive hematological malignancies.
METHODS
A national HTLV-1 register exists since 1989 in Spain, a non-endemic country with a large migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. The main features of all patients diagnosed with ATLL in Spain up to date are reported.
RESULTS
A total of 451 cases of HTLV-1 infection had been reported in Spain until the end of year 2022. ATLL had been diagnosed in 35 (7.8%). The current average incidence of ATLL in Spain is of two cases per year. Women represent 57% of ATLL patients. Mean age at diagnosis was 47 years-old. Roughly 57% were Latin Americans and 26% Africans. At diagnosis, the majority presented with acute or lymphoma clinical forms. Survival was shorter than one year in most of them. Mean HTLV-1 proviral load was significantly greater in ATLL patients than in asymptomatic HTLV-1 carriers (2,305 vs 104 copies/10 PBMC). HTLV-1 subtyping in 6 ATLL patients found the 1a transcontinental variant (n = 4) and the Japanese variant (n = 2). All ATLL patients were negative for HIV-1, did not develop HTLV-1-associated myelopathy and were not transplant recipients.
CONCLUSION
The rate of ATLL is very low in Spain and mostly associated to migrants from HTLV-1 endemic regions. Given the poor clinical outcome of ATLL, HTLV-1 testing should be performed at least once in all migrants coming from HTLV-1 endemic countries and in natives who have lived in or had sex partners from such regions.
Topics: Adult; Female; Humans; Male; Middle Aged; African People; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; Leukocytes, Mononuclear; Spain
PubMed: 37660433
DOI: 10.1016/j.jcv.2023.105578 -
Current Treatment Options in Oncology Aug 2023Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive subtype of peripheral T-cell lymphoma developing after many years of chronic, asymptomatic infection with the... (Review)
Review
Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive subtype of peripheral T-cell lymphoma developing after many years of chronic, asymptomatic infection with the retrovirus human T-cell lymphotropic virus type 1 (HTLV-1). HTLV-1 is endemic to certain geographic areas of the world, and primary infection generally occurs in infancy through mother-to-child transmission via breastfeeding. In less than 5% of infected individuals, a decades-long pathogenic process culminates in the development of ATL. Aggressive subtypes of ATL are life-threatening and challenging to treat, with median overall survival typically less than 1 year in the absence of allogeneic hematopoietic cell transplantation (alloHCT). Owing to the rarity of this illness, prospective large-scale clinical trials have been challenging to perform, and treatment recommendations are largely founded upon limited evidence. Herein, we review the current therapeutic options for ATL, providing a broad literature overview of the foremost clinical trials and reports of this disease. We emphasize our own treatment paradigm, which is broadly based upon disease subtype, patient fitness, and intent to perform alloHCT. Finally, we highlight recent advances in understanding ATL disease biology and important ongoing clinical trials that we foresee as informative and potentially practice-changing.
Topics: Adult; Humans; Female; Leukemia-Lymphoma, Adult T-Cell; Prospective Studies; Infectious Disease Transmission, Vertical; Human T-lymphotropic virus 1; Lymphoma
PubMed: 37300656
DOI: 10.1007/s11864-023-01111-1 -
Retrovirology May 2023Most proteins expressed by endogenous and exogenous retroviruses are encoded in the sense (positive) strand of the genome and are under the control of regulatory... (Review)
Review
Most proteins expressed by endogenous and exogenous retroviruses are encoded in the sense (positive) strand of the genome and are under the control of regulatory elements within the 5' long terminal repeat (LTR). A number of retroviral genomes also encode genes in the antisense (negative) strand and their expression is under the control of negative sense promoters within the 3' LTR. In the case of the Human T-cell Lymphotropic Virus 1 (HTLV-1), the antisense protein HBZ has been shown to play a critical role in the virus lifecycle and in the pathogenic process, while the function of the Human Immunodeficiency Virus 1 (HIV-1) antisense protein ASP remains unknown. However, the expression of 3' LTR-driven antisense transcripts is not always demonstrably associated with the presence of an antisense open reading frame encoding a viral protein. Moreover, even in the case of retroviruses that do express an antisense protein, such as HTLV-1 and the pandemic strains of HIV-1, the 3' LTR-driven antisense transcript shows both protein-coding and noncoding activities. Indeed, the ability to express antisense transcripts appears to be phylogenetically more widespread among endogenous and exogenous retroviruses than the presence of a functional antisense open reading frame within these transcripts. This suggests that retroviral antisense transcripts may have originated as noncoding molecules with regulatory activity that in some cases later acquired protein-coding function. Here, we will review examples of endogenous and exogenous retroviral antisense transcripts, and the ways through which they benefit viral persistence in the host.
Topics: Humans; Human T-lymphotropic virus 1; Deltaretrovirus; Viral Proteins; Promoter Regions, Genetic; HIV-1
PubMed: 37194028
DOI: 10.1186/s12977-023-00622-x -
Journal of Neurovirology Aug 2023Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus known to be associated with adult T-cell lymphoma and HTLV-1-associated myelopathy/tropical spastic...
Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus known to be associated with adult T-cell lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Previous researches and brain imaging techniques have suggested cognitive abnormalities as well as brain damage in individuals infected with this virus. Given the insufficient amount of studies on how this virus can impact the affected person's cognition, we aimed to assess and compare the cognitive abnormalities of HAM/TSP patients, asymptomatic HTLV-1 carriers, and healthy controls. This cross-sectional study was conducted on 51 patients divided into 3 groups; a group of HAM/TSP patients, a group of asymptomatic HTLV-1 carriers, and an uninfected control group. Each group contained 17 members. The cognitive state of the studied population was assessed using the Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), Rey-Osterrieth complex figure test (ROCF), the "Verbal Fluency Test" and the "Trail Making Test" (TMT) components of the Delis-Kaplan executive function system (D-KEFS) test, the Rey Auditory Verbal Learning Test (RAVLT), and digit span memory test. Patients diagnosed with HAM/TSP received significantly lower scores on the SDMT, ROCF, TMT, RAVLT, digit span memory test, and the orientation, calculation, and recall component of the MMSE assessment (p-value < 0.001). In addition, the asymptomatic HTLV-1 carriers obtained lower scores on the SDMT, ROCF, digit span memory test, and the orientation, calculation, and recall component of the MMSE assessment compared to the control group (p-value < 0.001). Overall, the findings suggest that HAM/TSP, or an asymptomatic infection with HTLV-1 could lead to cognitive deficits in the affected individuals. This can further emphasize the importance of assessing the cognitive function and psychiatric abnormalities of those infected with this virus.
Topics: Adult; Humans; Human T-lymphotropic virus 1; Cross-Sectional Studies; Paraparesis, Tropical Spastic; Cognition Disorders; Cognition; HTLV-I Infections
PubMed: 37204651
DOI: 10.1007/s13365-023-01139-x -
Frontiers in Immunology 2022Exogenous retroviruses such as human immunodeficiency virus type 1 (HIV-1), human T-cell leukemia virus type 1 (HTLV-1) and bovine leukemia virus (BLV) can cause various... (Review)
Review
Exogenous retroviruses such as human immunodeficiency virus type 1 (HIV-1), human T-cell leukemia virus type 1 (HTLV-1) and bovine leukemia virus (BLV) can cause various diseases including immunodeficiency, inflammatory diseases and hematologic malignancies. These retroviruses persistently infect their hosts. Therefore, they need to evade host immune surveillance. One way in which these viruses might avoid immune detection is to utilize functional RNAs, rather than proteins, for certain activities, because RNAs are not recognized by the host immune system. HTLV-1 encodes the () gene in the antisense strand of the provirus. The HBZ protein is constantly expressed in HTLV-1 carriers and patients with adult T-cell leukemia-lymphoma, and it plays critical roles in pathogenesis. However, not only encodes this protein, but also functions as mRNA. Thus, gene mRNA is bifunctional. HIV-1 and BLV also encode long non-coding RNAs as antisense transcripts. In this review, we reshape our current understanding of how these antisense transcripts function and how they influence disease pathogenesis.
Topics: Basic-Leucine Zipper Transcription Factors; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; RNA, Messenger; Retroviridae Proteins
PubMed: 35572593
DOI: 10.3389/fimmu.2022.875211 -
Modern Pathology : An Official Journal... Aug 2023Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in...
Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in the 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (positive: CD2, CD3, CD5, CD4, and CD25; negative: CD7, CD8, and cytotoxic markers; and partially positive: CD30, CCR4, and FOXP3). However, limited studies are available on the expression of these markers, and their mutual relationship remains unknown. Furthermore, the expression status of novel markers associated with T-cell lymphomas, including Th1 markers (T-bet and CXCR3), Th2 markers (GATA3 and CCR4), T follicular helper markers (BCL6, PD1, and ICOS), and T-cell receptor (TCR) markers, and their clinicopathologic significance is unclear. In this study, we performed >20 immunohistochemical stains in 117 ATLL cases to determine the comprehensive immunophenotypic profile of ATLL, which were compared on the basis of clinicopathologic factors, including morphologic variants (pleomorphic vs anaplastic), biopsy locations, treatments, Shimoyama classification-based clinical subtype, and overall survival. CD3+/CD4+/CD25+/CCR4+ was considered a typical immunophenotype of ATLL, but approximately 20% of cases did not conform to this pattern. Simultaneously, the following new findings were obtained: (1) most cases were negative for TCR-β and TCR-δ (104 cases, 88.9%), indicating the usefulness of negative conversion of TCR expression to provide differentiation from other T-cell tumors; (2) the positivity of CD30 and CD15 and the negativity of FOXP3 and CD3 were significantly associated with anaplastic morphology; and (3) atypical cases, such as T follicular helper marker-positive (12 cases, 10.3%) and cytotoxic molecule-positive cases (3 cases, 2.6%), were identified. No single markers could predict the overall survival among patients with acute/lymphoma subtypes of ATLL. The results of this study illustrate the diversity of ATLL phenotypes. In T-cell tumors occurring in HTLV-1 carriers, the possibility of ATLL should not be eliminated even when the tumor exhibits an atypical phenotype, and the confirmation of HTLV-1 in the tissue is recommended.
Topics: Adult; Humans; Leukemia-Lymphoma, Adult T-Cell; Human T-lymphotropic virus 1; Lymphoma; Lymphoma, T-Cell; Forkhead Transcription Factors
PubMed: 36997002
DOI: 10.1016/j.modpat.2023.100169