Human T-cell Lymphotropic Virus Research Articles

Human T-cell lymphotropic virus type 1 transmission dynamics in rural villages in the Democratic Republic of the Congo with high nonhuman primate exposure.

The Democratic Republic of the Congo (DRC) has a history of nonhuman primate (NHP) consumption and exposure to simian retroviruses yet little is known about the extent of zoonotic simian retroviral infections in DRC. We examined the prevalence of human T-lymphotropic viruses (HTLV), a retrovirus group of simian origin, in a large population of persons with frequent NHP exposures and a history of simian foamy virus infection. We screened plasma from 3,051 persons living in rural villages in central DRC using HTLV EIA and western blot (WB). PCR amplification of HTLV tax and LTR sequences from buffy coat DNA was used to confirm infection and to measure proviral loads (pVLs). We used phylogenetic analyses of LTR sequences to infer evolutionary histories and potential transmission clusters. Questionnaire data was analyzed in conjunction with serological and molecular data. A relatively high proportion of the study population (5.4%, n = 165) were WB seropositive: 128 HTLV-1-like, 3 HTLV-2-like, and 34 HTLV-positive but untypeable profiles. 85 persons had HTLV indeterminate WB profiles. HTLV seroreactivity was higher in females, wives, heads of households, and increased with age. HTLV-1 LTR sequences from 109 persons clustered strongly with HTLV-1 and STLV-1 subtype B from humans and simians from DRC, with most sequences more closely related to STLV-1 from Allenopithecus nigroviridis (Allen's swamp monkey). While 18 potential transmission clusters were identified, most were in different households, villages, and health zones. Three HTLV-1-infected persons were co-infected with simian foamy virus. The mean and median percentage of HTLV-1 pVLs were 5.72% and 1.53%, respectively, but were not associated with age, NHP exposure, village, or gender. We document high HTLV prevalence in DRC likely originating from STLV-1. We demonstrate regional spread of HTLV-1 in DRC with pVLs reported to be associated with HTLV disease, supporting local and national public health measures to prevent spread and morbidity.

Global expression of noncoding RNome reveals dysregulation of small RNAs in patients with HTLV-1\u2013associated adult T-cell leukemia: a pilot study

BackgroundAdult T cell lymphoma/leukemia (ATLL) is a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus-1 (HTLV-1). Small RNAs (sRNAs), including microRNAs (miRNAs), play a pivotal role in the initiation and development of hematological malignancies and may represent potential therapeutic target molecules. However, little is known about how these molecules impact the pathogenesis of ATLL. In this study, we aimed to identify sRNA expression signatures associated with ATLL and to investigate their potential implication in the pathophysiology of the disease.MethodsSmall-RNAseq analysis was performed in peripheral blood mononuclear cells from HTLV-1- associated ATLL (n = 10) in comparison to asymptomatic carriers (n = 8) and healthy controls (n = 5). Sequencing was carried out using the Illumina MiSeq platform, and the deregulation of selected miRNAs was validated by real-time PCR. Pathway analyses of most deregulated miRNA were performed and their global profiling was combined with transcriptome data in ATLL.ResultsThe sequencing identified specific sRNAs signatures associated with ATLL patients that target pathways relevant in ATLL, such as the transforming growth factor-(βTGF-β), Wnt, p53, apoptosis, and mitogen-activated protein kinase (MAPK) signaling cascades. Network analysis revealed several miRNAs regulating highly connected genes within the ATLL transcriptome. miR-451-3p was the most downregulated miRNA in active patients.ConclusionsOur findings shed light on the expression of specific sRNAs in HTLV-1 associated ATLL, which may represent promising candidates as biomarkers that help monitor the disease activity.

Oncogenic viruses and cancer

Oncogenic viruses (oncoviruses) are implicated in approximately 12% of all human cancers. Currently, the viruses known to cause human cancer are: Hepatitis B and C viruses (HBV and HCV), Human Papillomaviruses (HPV), Merkel Cell Polyomavirus (MCV), Human Herpesvirus-8 (HHV-8), Epstein-Barr Virus (EBV) and Human T-cell lymphotropic virus-1 (HTLV-1). However, oncoviruses are not complete carcinogens, need additional factors andisplay different roles in transformation. Oncoviruses can directly disrupt important regulatory cell genes by inserting virus genom into the DNA of the host cell. They also contain their own genes that damage the regulation of the cell. Some viruses have v-onc that cause disregulation of cellular processes and can lead to cancerous growth.

Brazilian Protocol for Sexually Transmitted Infections 2020: human T-cell lymphotropic virus (HTLV) infection.

This article addresses the Human T-lymphotropic virus (HTLV). This subject comprises the Clinical Protocol and Therapeutic Guidelines for Comprehensive Care for People with Sexually Transmitted Infections, published by the Brazilian Ministry of Health. HTLV-1/2 infection is a public health problem globally, and Brazil has the largest number of individuals living with the virus. HTLV-1 causes several clinical manifestations of neoplasm (adult T-cell leukemia/lymphoma) and inflammatory nature, such as HTLV-1-associated myelopathy and other manifestations such as uveitis, arthritis, and infective dermatitis. These pathologies have high morbidity and mortality and negatively impact the quality of life of infected individuals. This review includes relevant information for health authorities professionals regarding viral transmission, diagnosis, treatment, and monitoring of individuals living with HTLV-1 and 2 in Brazil.

Identification of bovine leukemia virus in raw milk samples in North-West of Iran.

Bovine leukemia virus (BLV) is one of the most important carcinogenic viruses genetically related to the human T-cell lymphotropic viruses (HTLV-1 and HTLV-2). The virus infects type B lymphocytes and creates lymph glands tumors. Recently, the association between the presence of this virus and breast cancer has been addressed in humans. Here, we studied the prevalence of BLV in the samples of raw milk of native Iranian and Iranian-foreign cows in traditional, semi-industrial and industrial dairy farms in rural and urban areas of Zanjan province. Raw milk samples of cows were collected manually in sterile tubes. The samples were tested by nested-PCR method. Forty samples (9.93%) out of 403 samples showed BLV contamination. In this study, nested-PCR was successfully applied to determine the level of contamination in raw milk samples from cows infected with BLV. Furthermore, a relatively high rate of BLV infection was found in dairy cows in Zanjan province, northwestern of Iran.

Co-expression of HBZ, TAX and FOXp3 and HTLV-1-associated myelopathy/ tropical spastic paraparesis development in HTLV-1-infected individuals: A systematic review

Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been reported that the HTLV-1 proteins (specifically TAX and HBZ) can modulate FOXp3, resulting in an immune imbalance that can favor the progression of HAM/TSP. This review aims to summarize the literature in order to clarify the relationship between the expression of HTLV-1 mRNAs and/or viral proteins (TAX and HBZ) with the expression of mRNA and/or protein FOXp3 and their correlation with HAM/ TSP development. This systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The search strategy was performed on the Medical Literature Analysis and Retrieval System Online and Latin American and Caribbean Literature in Health Sciences Platform using subject descriptors. After screening, six articles were included in this review. The studies suggested that TAX and HBZ have a directly proportional correlation with FOXp3 in individuals with HAM/TSP, which also presented an increased expression of FOXp3 compared to asymptomatic controls and/or healthy donors. This systematic review indicates that TAX and HBZ can interact with FOXp3 and that interaction may influence HAM/ TSP development.

HTLV-1-Associated Lymphoma Presented as Massive Lymphadenopathy.

Adult T-cell leukemia/lymphoma is an aggressive T-cell malignancy caused by the long-term infection of human T-cell lymphotropic virus type 1 (HTLV-1). Our understanding of clinical features still largely relies on the Shimoyama classification developed 30 years ago, which described the 4 clinical subtypes (the smoldering, chronic, lymphoma, and acute types) based on the manifestations of lymphocytosis, elevated lactate dehydrogenase, hypercalcemia, lymphadenopathy, and involvement of the skin, lung, liver, spleen, central nervous system, bone, ascites, pleural effusion, and gastrointestinal tract. HTLV-1-associated lymphoma has a variety of presentations but the presentation of massive lymphadenopathy and compression symptoms is rare and has not been emphasized in the literature. In this article, we describe 2 cases of adult T-cell leukemia/lymphomas that presented with massive cervical nodes or mediastinal nodes with compressing symptoms as the major presenting clinical features. Clinicians should remain aware of this type of presentation by HTLV-1-associated lymphoma, especially in patients who came from endemic areas, even if not all clinical features are present and particularly with hypercalcemia and lytic bone lesions.

Therapeutic effects of virtual reality video gaming on functional mobility, balance, and gait speed in individuals with tropical spastic paraparesis: A randomized crossover clinical trial

INTRODUCTION: Individuals with human T-cell lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) experience sensorimotor alterations, which can affect functional performance. Virtual reality (VR) videogaming is a therapeutic option, though there is scarce evidence for its use in this population. We aimed to investigate the therapeutic effects of a VR video game on functional mobility, balance, and gait speed in individuals with HAM/TSP. METHODS: We conducted a blinded, crossover clinical trial comprising 29 individuals with HAM/TSP and randomized them into two groups: (1) early therapy: rehabilitative protocol started immediately after the initial evaluation and (2) late therapy: rehabilitative protocol started 10 weeks later. We assessed all participants for balance using the Berg Balance Scale (BBS) scores, functional mobility using the Timed Up and Go (TUG) test, and gait speed using video camera and CvMob software. Differences were considered significant if p<0.05. RESULTS: The early therapy group individuals presented with higher BBS scores (p=0.415), less TUG times (p=0.290), and greater gait speed (p=0.296) than the late therapy group individuals. CONCLUSIONS: VR videogaming is a useful option for rehabilitative therapy in individuals with HAM/TSP; it positively affects balance, functional mobility, and gait speed.

Hairy Projections on Non Hairy Cells- A Case Report

Adult T-Cell Leukaemia/Lymphoma (ATLL) is a mature T-cell neoplasm. It is caused by human retrovirus Human T-cell Lymphotropic Virus Type 1(HTLV-1). The neoplastic cells after monoclonal integration begin to express T-cell associated antigens namely CD2, CD3 and CD5. These leukaemic cells are highly pleomorphic in light microscopic appearance and also they have a highly variable clinical presentation ranging from acute to lymphomatous to chronic to smouldering. There is a chance of missed or miss diagnosis due to their morphological and clinical heterogeneity and specialised test like immunophenotyping or flow cytometry is essential for exact categorisation. Authors hereby, report a case of 45-year-old female patient suffering from ATLL whose peripheral smear showed leukaemic cells with unusual hairy projections resembling hairy cell leukaemia posing diagnostic dilemma.

Dual intestinal parasitosis unmasked by treatment for gastrointestinal sarcoidosis

The symptoms and complications of intestinal parasitosis can occur with long-term corticosteroid therapy. We highlight the case of a young man who developed chronic gastrointestinal (GI) symptoms of diarrhea, crampy abdominal pain, and vomiting while on treatment for multisystemic sarcoidosis with corticosteroids. His symptoms were initially thought to be related to the gastrointestinal manifestations of sarcoidosis, but further evaluation revealed a combined case of intestinal strongyloidiasis and giardiasis as well as previously undiagnosed human T-cell lymphotropic virus (HTLV -1) infection. This distinctive case of dual intestinal parasitosis highlights the need for clinicians to maintain a high level of awareness to screen for intestinal parasites, particularly Strongyloides when prescribing corticosteroids in the long term given the potential risk of hyperinfection in the setting of immunosuppression..

HTLV-1 infection in acute t- lymphocytic leukemia/lymphoma

ABSTRACTAdult T- lymphocyte leukemia/ lymphoma (ATLL), described by Uchiyama et al. in 1977, is a distinct neoplasia of peripheral T-lymphocytes caused by human T-cell lymphotropic virus type 1 (HTLV-1). The authors describe the case of a 75-year-old female patient who presented with fever, chills, and altered mental status. The peripheral blood morphology showed large atypical lymphocytes with multilobed nuclei and flow cytometry consistent with ATLL. The authors discuss the pathophysiology, differential diagnosis, and subtypes of ATLL in addition to the diagnostic approach using flow cytometry when bone marrow biopsy is not available and modalities of treatment.

Low frequency of CD94/NKG2A+ T lymphocytes in patients with HTLV-1–associated myelopathy/tropical spastic paraparesis, but not in asymptomatic carriers

AbstractHuman natural killer (NK)–cell receptors are expressed by NK cells and some T cells, primarily TCR+CD8+ cytotoxic T lymphocytes (CTLs). Inhibitory NK cell receptors (iNKRs) can down-regulate antigen-mediated T-cell effector functions, including cytotoxic activity and cytokine release. In the present study we demonstrate that CD3+ T cells that bind tetramers of HLA-E and express its ligand, the NK-cell inhibitory receptor CD94/NKG2A, were significantly decreased in frequency in patients with human T-cell lymphotropic virus 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) but not in asymptomatic HTLV-1 carriers. These cells were either αβ or γδ T cells. T-cell receptor (TCR) Vβ-specific reverse transcription–polymerase chain reaction and spectratyping analysis revealed that the TCR repertoire in directly isolated HLA-E tetramer–positive cells from peripheral blood mononuclear cells was skewed in both HTLV-1–infected and healthy individuals. However, oligoclonally or monoclonally expanded levels of TCR Vβwere more frequently detected within HTLV-1–infected individuals than healthy controls. Importantly, HLA-E tetramer–positive or NKG2A+ T cells from HTLV-1 patients do not express Tax and display different TCR usage from the immunodominant Tax11-19–specific CD8+ T cells, suggesting that they do not encounter HTLV-1–infected cells. The expression of NK cell–associated receptors by clonally expanded CD8+ T cells during chronic viral infection suggests that these receptors play a role in regulating CD8+ T cell–mediated antiviral immune responses and that a decrease of this cell subset results in an increased risk of inflammatory diseases such as HAM/TSP.

Extracellular Vesicles in HTLV-1 Communication: The Story of an Invisible Messenger

Human T-cell lymphotropic virus type 1 (HTLV-1) infects 5–10 million people worldwide and is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as other inflammatory diseases. A major concern is that the most majority of individuals with HTLV-1 are asymptomatic carriers and that there is limited global attention by health care officials, setting up potential conditions for increased viral spread. HTLV-1 transmission occurs primarily through sexual intercourse, blood transfusion, intravenous drug usage, and breast feeding. Currently, there is no cure for HTLV-1 infection and only limited treatment options exist, such as class I interferons (IFN) and Zidovudine (AZT), with poor prognosis. Recently, small membrane-bound structures, known as extracellular vesicles (EVs), have received increased attention due to their potential to carry viral cargo (RNA and proteins) in multiple pathogenic infections (i.e., human immunodeficiency virus type I (HIV-1), Zika virus, and HTLV-1). In the case of HTLV-1, EVs isolated from the peripheral blood and cerebral spinal fluid (CSF) of HAM/TSP patients contained the viral transactivator protein Tax. Additionally, EVs derived from HTLV-1-infected cells (HTLV-1 EVs) promote functional effects such as cell aggregation which enhance viral spread. In this review, we present current knowledge surrounding EVs and their potential role as immune-modulating agents in cancer and other infectious diseases such as HTLV-1 and HIV-1. We discuss various features of EVs that make them prime targets for possible vehicles of future diagnostics and therapies.

Qualitative evidence synthesis of values and preferences to inform infant feeding in the context of non-HIV transmission risk.

Breastfeeding is recommended by many organisations, but feeding choices can take on complexity against a backdrop of a transmissible infection risk. The aim of this synthesis is to explore what is known about the values and preferences of pregnant women, mothers, family members and health practitioners, policy makers and providers (midwives) concerning feeding when there is a risk of Mother-to-Child transmission [MTCT] of an infectious disease (other than HIV/AIDS) to infants (0-2 years of age). A qualitative evidence synthesis and GRADE CERQual assessment of relevant studies of values and preferences regarding infant feeding options in the context of non-HIV MTCT risk. The synthesis included eight qualitative studies. Four studies focussed on human T-cell lymphotropic virus type 1 (HTLV-1), three studies on Ebola, and one study on influenza vaccination. Mothers reported feeling sadness and guilt at not breastfeeding, while recognising that it was important for the health of their baby not to breastfeed. Mothers were reportedly appreciative of the provision of appropriate facilities, and the advice of those health professionals who knew about the diseases, but felt other professionals lacked knowledge about the transmission risk of conditions such as HTLV-1. All groups expressed concerns about social perceptions of not breastfeeding, as well as the alternatives. The evidence was coherent and relevant, but there were serious concerns about adequacy and methodological limitations, such as potential social desirability bias in some studies. This synthesis describes the reported values and preferences of pregnant women, mothers, and others concerning feeding when there is a risk of Mother-to-Child transmission (MTCT) of an infectious disease (other than HIV/AIDS) to an infant when breastfeeding. However, the evidence in the peer-reviewed literature is limited both in quality and quantity.

A case series on UCB seroprevalance of Human T-lymphotropic virus

Background: Human T-cell lymphotrophic Virus 1 (HTLV)-1 is a delta retrovirus endemic in the Caribbean, parts of South America, West Africa, Asia, and Oceania. In the Caribbean, 2-5% of adults are infected. Breast feeding is the most common form of transmission. HTLV-1 is an abbreviation for human T-cell lymphotropic virus type 1, also called human T-cell leukemia type 1, a virus that has been implicated in several kinds of diseases, including HTLV-1-associated myelopathy, and as a virus cancer link for leukemia (T-cell leukemia/lymphoma). Methods and materials: The trial was conducted at Cord life Sciences Cord blood Bank from a period from 30 April2018 to 30th April, 2019.A total of 8400 umbilical cord blood donors were studied. All subjects were counseled pre-donation about the all the serology tests that would be conducted. The cord blood was transported to the cord blood bank maintaining complete cold chain and our TAT of 72 hours was maintained without any exceptions during the trial. Each sample was tested by Chemiluminescence technology three times and the results were analysed. Another fresh sample was then taken from the suspected subjects and tested via Chemiluminescence technology in the same setting as before. Thereafter results were analysed. Results: 10 umbilical cord blood donors were positive (above cut off 0. 8 samples The repeat sample which were redrawn within 72 hours of previous sample collection were tested in the same setting under similar circumstances with the same kit batch and it too tested positive for all 10 samples. Conclusion: HTLV-1 seroprevalence in adults is estimated to be at least 1–2% The main highly endemic areas are the south-western part of Japan, some parts of the Caribbean and its surroundings regions.We recommend that mothers with positive or indeterminate supplemental test results have follow-up NAT. We recommend that mothers with positive or indeterminate supplemental test results have must be followed up on a priority basis Nucleic Acid Testing or Western Blot assay.

Chapter XX Antiviral Treatment and Cancer Control.

Hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), Epstein-Barr virus (EBV), human T-cell lymphotropic virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), and Merkel cell polyomavirus (MCV) contribute to about 10-15% global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infection have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, KSHV, and HTLV-1 had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA interference-based therapies for treating HPV-associated infection or cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies in a real-world setting are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.

Molecular Epidemiology of HIV-1 and HTLV-1/2 Among Female Sex Workers in Four Cities in the State of Para, Northern Brazil.

Female sex workers (FSWs) represent a key population for the acquisition of sexually transmitted infections (STI) due to their social vulnerability and the risks associated with their occupation. This study was conducted to describe the sociodemographic characteristics and sexual behavior among FSWs in cities in northern Brazil, to determine the prevalence of human immunodeficiency virus 1 (HIV-1) and human T-cell lymphotropic virus (HTLV-1/2) infections and to identify the circulating subtypes of these agents in this key population. A cross-sectional study using the Time Location Sampling (TLS) method was conducted among 339 FSWs in cities in the state of Pará from 2005 to 2006. Serological and molecular tests were performed to identify infections and viral subtypes, and bivariate and multivariate analyses were conducted to identify risk factors. Most FSWs were young, single, less educated and had at least one child. The prevalence of antibodies against HIV-1 and HTLV-1 was 2.3 and 1.7%, respectively. HIV-1 subtypes B (87.5%) and F1 (12.5%) were identified among FSWs, as were Cosmopolitan subtype (1a) and Transcontinental subgroup (A). Unprotected sex and illicit drug use were associated with HIV-1 and HTLV-1 infections using bivariate and multivariate analyses, and age ≥27 years was associated only with HIV. The important information highlighted here clearly indicates that the lack of actions to control and prevent pathogens in FSWs and the lack of strategies for health promotion in key populations can further aggravate the epidemiological scenario of viral infections in remote areas with low human development indices. Neglecting these facts may be causing the spread of these two viruses and their respective subtypes in the general population of northern Brazil.

Impact of Human T-Cell Lymphotropic Virus Infection on Survival Following Stem Cell Transplantation

Human T-Cell Lymphotropic Virus (HTLV) Types 1 or 2 are delta retroviruses that may lead to complications including adult T-cell leukemia-lymphoma (ATLL) and HTLV-1-associated myelopathy (HAM). There is concern that immunosuppression may result in progression from an asymptomatic carrier state to ATLL or HAM. Data on the safety of stem cell transplantation (SCT) in patients with HTLV-1/2 infection are lacking. The Center for International Blood and Marrow Transplant Research (CIBMTR) was queried for all patients who tested positive for HTLV infection in the pre-transplantation workup and underwent either autologous SCT (AutoSCT) or allogeneic SCT (AlloSCT) between 2008-2017. The primary outcome was overall survival up to four years post-SCT, assessed using the Kaplan-Meier statistic. All analyses were univariate and did not adjust for differences in disease, disease stage or patients characteristics. In those who underwent AutoSCT, 54 (0.5%) patients were HTLV-positive and 9,837 were HTLV-negative. In those who underwent AlloSCT, 126 (0.7%) patients were HTLV-positive and 18,084 were HTLV-negative. In the HTLV-negative group, a larger proportion underwent AlloSCT for acute myeloid leukemia in the HTLV-negative group, while Non-Hodgkin lymphoma/other leukemia was more common in the HTLV-positive group (P&amp;lt;0.001). Additional patient demographics are listed in Table 1. No difference in overall survival (p=0.661) or non-relapse mortality (p=0.522) was noted following AutoSCT based on HTLV status. Following AlloSCT, univariate analysis showed the HTLV-positive patients had a statistically significant lower overall survival (Figure 1; p=0.013) and higher non-relapse mortality at year four (Figure 2; p=0.023). In conclusion, survival after AutoSCT seems unaffected by HTLV status. While the underlying indications for AlloSCT differed in HTLV-infected patients, decreased overall survival and increased non-relapse mortality were seen in HTLV-positive patients. Reasons for increased non-relapse mortality may include increased infectious complications or graft-versus-host disease. Further studies are needed to understand the relative contributions of these factors. Disclosures Janakiram: Takeda, Fate, Nektar: Research Funding. Sloan:Stemline: Consultancy; Abbvie: Consultancy.

Allogeneic Stem Cell Transplantation in a Large Urban Cohort of North-American Adult T-Cell Leukemia/Lymphoma

Introduction: Adult T-cell leukemia lymphoma (ATLL) is a rare hematologic malignancy caused by human T-cell lymphotropic virus (HTLV-1) with dismal cure rates and poor response to conventional chemotherapy. Allogeneic Hematopoietic Stem Cell Transplantation (AlloSCT) is the only therapeutic option which may offer the chance of long-term remission and cures in a subset of patients. We sought to investigate the outcomes of transplantation in one of the largest cohorts in North America. Methods: A retrospective chart review study was conducted using the North-American ATLL and the Hematopoietic Precursor Cell transplantation databases at Montefiore Medical Center from 2011 to 2020. Variables collected include age, sex, ethnicity, ATLL subtype, molecular profile, previous treatments, conditioning regimens, type of transplant, immunosuppressive regimen, progression free survival (PFS) post-transplant and overall survival (OS) post-transplant. Results: Fourteen patients with ATLL who received an AlloSCT from 2011-2020 were identified. Fifty-seven percent (8/14) of patients were male. Seventy-one percent (10/14) of patients were African American and twenty-nine percent (4/14) were Hispanic. Median age was 51 years. Sixty-four percent (9/14) of patients had Stage IV disease at the time of diagnosis. Forty-three percent (6/14) patients had acute and fifty-seven percent (8/14) had lymphomatous ATLL. Almost all patients (92%) were treated initially with EPOCH combination chemotherapy. Twenty-eight percent (4/14) of patients received interferon/zidovudine as bridge-to-transplant. Fifty-seven percent (8/14) of patients achieved complete remission (CR) prior to AlloSCT, 7% (1/14) were in partial remission, and 28% (4/14) were relapsed or refractory. Forty-three percent (6/14) of patients received SCT from a matched-related donor (MRD), 36% (5/14) from a haplo-identical donor and 21% (3/14) from a matched-unrelated donor (MUD). Ninety-three percent (13/14) of patients received a reduced-intensity conditioning (RIC) regimen pre-transplantation. Seven percent (1/14) received a myeloablative conditioning (MAC) regimen. RIC regimens consisted of fludarabine with melphalan +/- anti-thymocyte globulin (ATG) or fludarabine with cyclophosphamide with total-body irradiation in doses less than 500 cGy. Patients receiving haplo-identical SCT also received post-transplant cyclophosphamide (PTCy) for prevention of graft vs host disease (GVHD). The MAC regimen used included busulfan with cyclophosphamide at myeloablative doses. Twenty-eight percent (4/14) of patients relapsed post-alloSCT with a median relapse-free survival of 6 months (range 4-18 months). The median OS of the whole cohort was 27 months (8-82 months). Graft-versus-host disease (GVHD) developed in 28% (4/14) percent of patients. The most common manifestation was skin GVHD. Fifty-percent (7/14) of the patients are surviving to-date. Transplant-related mortality (TRM) at day 100 was 21% (3/14) of patients. Causes of death were complex and included several diagnoses in certain patients. The most frequent diagnoses associated with death were infection (28%), graft failure (14%), GVHD (14%), veno-occlusive disease of the liver (VOD) (7%), disease progression (14%) and unknown due to patient lost to follow-up (14%). The main infectious events included fungal (2), bacterial (1), and COVID-19 (1) infection. Forty-three percent (6/14) of patients remain in complete remission to date. Conclusions: Allogeneic Stem Cell Transplantation offers long-term survival with a TRM of 21% in a disease with an inherently dismal prognosis. AlloSCT using several graft sources, is thus, a safe and well tolerated treatment modality and offers long term remissions. Disclosures Steidl: Pieris Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding; stelexis: Current equity holder in private company. Janakiram:ADC Therapeutics, FATE therapeutics, TAKEDA pharmaceuticals: Research Funding.

Characterization of the Blood and Bone Marrow Microbiome of MDS Patients and Associations with Clinical Features

To date, several malignancies of the lymphoid lineage have been linked with microbial infection. Indeed, lymphomas have been associated with the bacteria Helicobacter pylori, and T-cell leukemia and Burkitt's lymphoma have long been known to be commonly caused by viral infections (human T-cell lymphotropic virus 1 and Epstein-Barr virus (EBV), respectively). However, metagenomics research in myeloid malignancies has primarily focused on the roles of gut flora rather than on the tumor site itself (blood and bone marrow). Traditionally, human blood and bone marrow was considered to be normally sterile, and therefore microbiome analysis of these entities would only be performed when deleterious infection was suspected. However, evidence is now accumulating for a normal blood microbiome in healthy individuals. Given the growing number of established relationships in other malignancies between the microbiome at the tumor site and clinical characteristics, we hypothesized roles for the bone marrow microbiome in MDS patients. To this end, we extracted bacterial, fungal, and viral sequence from the bone marrow and blood of 640 MDS patients taken at diagnosis. Briefly, whole-genome sequencing (minimum coverage 100x) was performed on DNA extracted from each patient sample. Reads not aligning to the human genome were aligned to NCBI's database of known microbial reference genomes, and microbial species were assessed for presence and abundance in each sample. As expected, bacterial reads dominated, comprising 99.8% of all microbial reads, while viral reads were 2.73-fold as prevalent as fungal reads. We calculated microbial diversity (Shannon diversity index) on the genus and phylum levels for each patient. As has been reported in solid tumors, higher alpha-diversity is associated with favorable overall survival (age- and sex-adjusted P = 8.6 x 10-3; Figure 1A). Interestingly, individuals with normal karyotype had significantly higher alpha-diversity at the phylum level (Wilcoxon P = 0.002; Figure 1B), while those with deletion of chromosome 5q had significantly lower alpha-diversity (P = 2.2 x 10-5; Figure 1C). Among viral infections, EBV (formally Human gammaherpesvirus 4) was the most common, with 192 patients (30%) harboring EBV DNA sequence. Human cytomegalovirus (HCMV; formally Human gammaherpesvirus 5) and Human betaherpesvirus 6 infections were also observed, in 23% and 2% of patients, respectively. EBV infection was associated with worse overall survival (age- and sex-adjusted P = 0.037; Figure 1D). There was also a substantial dose effect, with higher EBV levels corresponding to poorer outcomes (P = 1.96 x 10-6). Mining the paired-end DNA reads for human-viral chimeras, we found multiple instances of EBV integration into the patient genome, suggesting a possible mechanism for EBV infection impacting patient outcomes. Bacterial composition was also analyzed, showing strong concordance between several pairs of phyla, suggesting synergy between these bacterial communities (Figure 1E). On the other hand, the Proteobacteria and Actinobacteria phyla were strongly discordant with one another (Figure 1E). Multiple studies have shown dominance of Proteobacteria in the circulating bacteriome of healthy individuals. In contrast, the MDS patients in our study showed a continuum between complete dominance of the Proteobacteria phylum and complete dominance of the Actinobacteria phylum (Figure 1F). Intriguingly, lower levels of Actinobacteria was strongly associated with the presence of various chromosomal aberrations, while the opposite was largely true for Proteobacterial abundance. As a result, the ratio of these two phyla abundances was strongly positively associated with normal karyotype and negatively associated with del(5q) (Table 1). Overall, our study provides evidence for roles of the bone marrow microbiome in phenotypes and may even influence outcomes of patients with MDS. Further research is required to determine: a) whether microbial content is cause or consequence of patient characteristics, and b) what the mechanisms are for these microbiome-clinical associations. Disclosures Maciejewski: Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.