Human Lymphotropic Virus Type Research Articles

Adult T-cell leukaemia/lymphoma in an adolescent patient: Expect the unexpected

This case study explores a clinicopathological presentation of Adult T-cell leukaemia/lymphoma (ATLL) at Tygerberg Hospital; a disease associated with adulthood noted in an adolescent patient. Adult T-cell leukaemia–lymphoma oncogenesis develops through a multistep process with an accumulation of mutations. Infection through human T-lymphotropic virus type 1 (HTLV-1) is the first step of a multistep process resulting in eventual clonal proliferation of mature T-cells. There is a long latency period of 20–50 years from the time of infection with HTLV-1 to the development of symptoms of ATLL; thus, ATLL is a malignancy associated with adulthood. The median age of diagnosis is 58, ranging from the third to ninth decade of life. This is an ideal learning case as it highlights the importance of recognising ATLL in children and young adults in our population.

SAT-LB309 Amphotericin B Induced Hypocalcemia in a Patient With Severe Hypercalcemia Due to Acute T-Cell Leukemia/Lymphoma

SAT-LB309 Amphotericin B Induced Hypocalcemia in a Patient With Severe Hypercalcemia Due to Acute T-Cell Leukemia/Lymphoma

Abstract IA15: Role of human papillomaviruses in carcinogenesis

Abstract Infectious agents represent a major group of risk factors for cancer development and contribute to about 15% of human cancers worldwide. Six viruses and one bacterium, i.e., human papillomavirus (HPV), hepatitis C virus (HCV), hepatitis B virus, human T-lymphotropic virus type I (HTLV-1), Epstein-Barr virus (EBV), Kaposi sarcoma-associated virus (KSHV), and Helicobacter pylori, have been clearly associated with human carcinogenesis. The mucosal high-risk (HR) HPV types are the etiologic factors of cervical cancers and subset of oropharyngeal cancers. In addition, ongoing studies concerning a subgroup of HPV types that infect the skin suggest their involvement, together with ultraviolet radiation (or solar exposure), in the development of nonmelanoma skin cancer (NMSC). Biologic studies have demonstrated that the products of two early genes from the HR HPV types, E6 and E7, play a key role in cancer development. Both viral oncoproteins are able to target several cellular pathways leading to the evasion of the immune surveillance and cellular transformation. These studies also substantially contributed to our understanding of key mechanisms involved in the normal life of the cell. In the last few years, we have performed additional studies on cutaneous and mucosal HPV types and have characterized novel oncogenic viral mechanisms involved in the evasion of the immune response and/or in cellular transformation. A few examples will be presented. Citation Format: Massimo Tommasino. Role of human papillomaviruses in carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA15.

Expression of TSLC1 in patients with HAM/TSP.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic myelopathy characterized by slowly progressive spastic paraparesis and urinary dysfunction. A few biomarkers in the cerebrospinal fluid are known to be related to disease activity, but no biomarker has been reported in peripheral blood. This study aims to explore the expression level of the adhesion molecule during the expression level of the adhesion molecule among HAM/TSP disease activity. In lymphocyte function-associated antigen 1 and DNAX accessory molecule 1, no variation in expression levels specific to HTLV-1 infection was observed in CD4-positive T cells; however, TSLC1 expression was higher in HAM patients than in asymptomatic carriers and non-infected persons. TSLC1 tended to be higher in patients whose symptoms were worsening. On the contrary, the expression level of TSLC1 in CD8-positive T cells was lower in HAM patients than in asymptomatic carriers, and this tendency was stronger in patients whose symptoms had deteriorated. No significant correlation was found between TSLC1 and either of the transcription factors Tax or HBZ in any T cell group. Therefore, TSLC1 expression in CD4-positive T cells might be a useful biomarker of HAM/TSP disease activity.

First Description of Seronegative HTLV-1 Carriers in Argentina.

In some areas of Argentina endemic for human T-lymphotropic virus type 1 (HTLV-1), tropical spastic paraparesis is frequent in subjects who lack antibodies against the virus; however, the relevance of this seronegative status in the country has not been investigated. In neighboring countries, HTLV-1 seronegative status has been described in patients with different diseases; however, data regarding features of seronegative HTLV-1 carriers are scarce. We investigated the seronegative status in 124 relatives of 28 HTLV-1 infected subjects from an endemic area in Northwest Argentina. Blood samples and clinical/epidemiological data were collected. Human T-lymphotropic virus type 1 infection was diagnosed by serology and long terminal repeat (LTR) sequence, env and tax gene detection. IgG anti-Tax HTLV-1 antibody, tax gene sequence, and DNA proviral load were also evaluated. Seventy-five percent of the 124 relatives were negative for HTLV-1/2 antibodies; 35.5% were also negative by molecular assays and 64.5% were negative for HTLV-1 LTR and env sequences, but positive for two sequences of HTLV-1 tax gene. Also, 35.7% of these subjects had IgG anti-Tax antibodies. The seronegative HTLV-1 status was significantly associated with male gender, youth, and sensory symptoms/autonomic nervous system dysfunction. High rates of seronegative symptomatic and asymptomatic HTLV-1 carriers in Argentina are described. The evidence highlights that HTLV-1 prevalence may be underestimated worldwide. Larger cohort studies are required to assess disease outcome in these seronegative subjects. Also, the findings emphasize the limitations of ongoing screening assays for diagnosis and blood safety. Therefore, algorithms for HTLV-1 diagnosis should include not only serological but also molecular assays.

Tackling HTLV-1 infection in ophthalmology: a nationwide survey of ophthalmic care in an endemic country, Japan

IntroductionJapan is the most endemic of the developed nations in terms of human T-lymphotropic virus type 1 (HTLV-1) infection. Japan has been tackling HTLV-1 infection and has made remarkable progress....

Dental care as a risk factor for transfusion transmissible infections in blood donors: a systematic review and meta-analysis.

The deferral policy for blood donation after dental care is based on the precautionary principle. The aim of this systematic review is to give an overview of the scientific evidence concerning the risk of transfusion transmissible infections (TTIs) after dental care. Four databases were searched: Medline, the Cochrane Library, Embase and Web of Science. Screening was independently performed by two reviewers. The quality of evidence was evaluated using the Grades of Recommendation, Assessment, Development and Evaluation principle. A meta-analysis was performed to assess the association between dental treatment and TTI markers. A total of 22 studies were included. Meta-analysis of 16 studies showed an increased association of TTIs with dental treatment, however with large heterogeneity. Subgroup analysis revealed a significant increased association of hepatitis B virus (HBV) with dental treatment [odds ratio 1.79, 95% confidence interval (1.48; 2.18)]. There was conflicting evidence concerning the risk of hepatitis C virus (HCV). One study could not demonstrate a statistically significant increased association of human T-lymphotropic virus type I with dental treatment. Three studies showed a significant increased association of HCV with tooth extraction [odds ratio 1.48, 95% confidence interval (1.11; 1.97)]. Finally, there is conflicting evidence concerning the risk of HBV or HCV after dental cleaning. One study could not demonstrate an association between HIV and dental cleaning. All evidence is of very low certainty and results cannot be considered precise. Studies of high quality concerning the risk of TTI after dental care in blood donors are scarce. An association of HBV after dental treatment and HCV after tooth extraction was demonstrated but evidence is of very low certainty. The currently identified studies are of too low certainty to make any suggestions regarding the value of deferral or deferral times.

Associations of Viral Seroreactivity with AIDS-Related Non-Hodgkin Lymphoma.

Infection with human immunodeficiency virus (HIV) is associated with substantially increased incidence of non-Hodgkin lymphoma (NHL). This risk may be driven, in part, by reduced immune control over viral infections in the setting of acquired immunodeficiency syndrome (AIDS), although the lymphomagenic mechanisms are not yet established. We used bead-based multiplex assays to measure antibody seroreactivity to 32 viral antigens representing 22 different viral infections (human herpesviruses 1-8, hepatitis B and C virus, human T-lymphotropic virus type-1, and human polyomaviruses) in two prospective HIV cohorts. Incident (n = 28) and prevalent (n = 38) AIDS-related NHL cases were matched by age, sex, race, and CD4 count to 67 HIV-positive control individuals without AIDS-NHL. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of AIDS-NHL with the number of different viruses to which an individual was seropositive and seroreactivity to individual antigens. Seropositivity to an increasing number of viruses was inversely associated with AIDS-NHL (OR per virus = 0.84, 95% CI = 0.72-0.98). Seroreactivity to herpes simplex virus 2 2mgG unique antigen (OR = 0.47; 95% CI = 0.23-0.97) and to WU polyomavirus viral capsid protein (OR = 0.26, 95% CI = 0.10-0.65) was significantly lower in AIDS-NHL cases compared to controls. In this evaluation of antibodies to multiple viruses, we observed an inverse association between seropositivity to a larger number of viruses and AIDS-NHL. While in need of further evaluation, our data raise the novel hypothesis that insufficient exposures or impaired humoral immune responses to viral infections may be associated with AIDS-related lymphomagenesis.

A pilot study to establish human T-cell leukemia virus type 1 (HTLV-1) carrier model using common marmoset (Callithrix jacchus).

For the diagnosis and treatment of adult T-cell leukemia/lymphoma (ATLL) caused by human T-lymphotropic virus type 1 (HTLV-1) are required therapeutic modalities urgently. Non-human primate models for ATLL would provide a valuable information for clinical studies. We did a pilot study to establish an ATLL non-human primate model using common marmosets (Callithrix jacchus). We inoculated HTLV-1-producing MT-2 cells into 9-month-old marmosets, either intraperitoneally or intravenously. We next administrated MT-2 cells into 13-month-old marmosets under cyclosporine A (CsA) treatment to promote infection. HTLV-1 infection was determined by measuring HTLV-1 antibody titer in the common marmosets. The HTLV-1 antibody titer increased in the intraperitoneally inoculated marmoset with or without CsA treatment, and it kept over five 5years though proviral copy number (proviral load, PVL) remained low throughout the study. We obtained HTLV-1 asymptomatic carriers of common marmosets by inoculating MT-2 cells.

Prevalence of Human T-Lymphotropic Virus Type 1 (HTLV-1) Infection among Patients with Hematologic Disorders – Serology and Molecular Based Cross- Sectional Study in Khartoum, Sudan

The human T-cell lymphotropic virus types-1 (HTLV -1) is well-established risk for the developing Hematological malignancies including adult T cell leukemia lymphoma (ATLL). The aim of this study is to evaluate the prevalence of HTLV-1 infection in patients with hematologic malignancies in Khartoum state by using serological and molecular approaches. During the period from April to September 2019 a total of 106 blood samples were obtained from Hematological Malignancy patients including AML, CML, CLL, ALL, MDS and ATLL. The presence of malignancy was confirmed by using IHC, Molecular and cytogenetic studies. Both males and females were included. A volume of 6 ml blood sample was collected from each patient and tested for the presence of anti-HTLV-1 antibodies using enzyme-linked immunosorbent assay (ELISA). Those with positive serology test were confirmed by detection of Proviral gene by using PCR. Data were analyzed by using spss version 19. The study participants were including 72 (67.9%) males and 34 (32.9%) females. The average age of the study population was 41± 12.4. The result of serology test reveals that out of 106 serum samples examined 7 (6.6%) were positive for HTLV-1 antibody test including 5 males and 2 females. All positive cases were confirmed by PCR and identified with the proviral pX-S gene. Of the HTLV-1 positive cases, three were diagnosed with CML, two were diagnosed with AML in addition to one male patient was diagnosed with ATLL as well as another one male patient diagnosed with CLL. In conclusion, our results show a similar prevalence of HTLV-1 infection in patients with hematologic disorders in comparison to other studies conducted on the African general population. Larger case control based studies with inclusion of more sample size are essential to corroborate the study evidence.

Association of TLR3 single nucleotide polymorphisms with susceptibility to HTLV-1 infection in Iranian asymptomatic blood donors

INTRODUCTION: The human T-lymphotropic virus type 1 (HTLV-1) has a single-stranded RNA genome and expresses specific proteins that have oncogenic potential. Approximately 15 to 20 million people worldwide have been infected by this virus. Changes in protein or gene expression are the effects of single nucleotide polymorphisms (SNPs) within the Toll-like receptor 3 (TLR3) gene. The function and efficacy of signal transduction also lead to modified immune responses. The present study aimed to investigate the association of SNPs within TLR3 (rs3775291 and rs3775296) with susceptibility to HTLV-1 infection in Iranian asymptomatic blood donors. METHODS: This study was performed on 100 HTLV-1-infected asymptomatic blood donors and 118 healthy blood donors. Genomic DNA from all participants was purified and then amplified using specific PCR primers. SNPs within TLR3 were evaluated using the restriction fragmentation length polymorphism technique, and the results were analyzed using SPSS software (version 22). RESULTS: The frequencies of the TLR3 (rs3775296) CC, CA, AA genotypes were 70%, 24%, and 6% in the patient group, and 50.8%, 44.9%, and 4.2% in the control group, respectively. There was a significant difference in the frequency distribution of TLR3 (rs3775296) genotypes and alleles, but not in the frequency distribution of TLR3 (rs3775291) genotypes between the patient and control groups. CONCLUSIONS: The TLR3 SNP rs3775296 was significantly associated with HTLV-1 infection and may be a protective factor against this viral infection.

Therapeutic responses to interferon-alpha in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP): Differing clinical responses to leukocyte-derived human interferon-alpha versus recombinant interferon-alpha

Introduction: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive spinal cord syndrome seen in patients infected by human T-lymphotropic virus type 1 (HTLV-1). Initial infection by the virus is usually asymptomatic. As the disease progresses, a se

Prevalence of transfusion-transmissible infections among blood donors in Riyadh: A tertiary care hospital-based experience

Background: Transfusion-transmissible infections (TTIs) such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Treponema pallidum are a serious threat to the safety of recipients. Materials and Methods: This was a retrospective analysis of 38,621 blood donors screened for TTIs between January 2016 and December 2018 at King Khalid University Hospital, Riyadh, Saudi Arabia. Viral serology comprised of detection of hepatitis B surface antigen (HBsAg) and anti-core HBV antibody (anti-HBc), HCV antibody, and HIV antigen/antibody assays. Nucleic acid testing for viral genetic material was performed using Roche Cobas TaqScreen MPX v2 (Roche Molecular Systems, NJ, USA.) on Cobas s201 system. T. pallidum infection was confirmed by a reactive T. pallidum hemagglutination assay. Results: Of the total donors, 37,202 (96%) were males and 1419 (4%) were females, with a mean age of 30.3 ± 5 years. Majority of the donors (27,963; 72.4%) were Saudi nationals, whereas 10,658 (27.6%) individuals were of other nationalities comprising 24,356 (63%) volunteers and 14,265 (37%) repeat donors. The overall prevalence of TTIs among blood donors was 0.7%, with a prevalence of HBsAg of 0.29%, anti-HBc of 4%, HCV of 0.3%, HIV of 0.005%, human T-lymphotropic virus type I and II of 0.002%, and T. pallidum of 0.02%. No significant differences were observed in the annual prevalence rates of TTIs. Conclusion: Relatively low prevalence rates of TTIs were observed among the blood donors during the study period.

Surveillance of human retroviruses in blood samples from patients with hepatitis B and C in São Paulo, Brazil.

INTRODUCTION Human retroviruses and the hepatitis B and C viruses (HBV and HCV, respectively) share routes of transmission; thus, coinfections occur and could alter subsequent disease outcomes. A preliminary study on human T-lymphotropic virus types 1 and 2 (HTLV-1/2) in serum samples from HBV- and HCV-infected individuals in São Paulo revealed 1.3% and 5.3% rates of coinfection, respectively. These percentages were of concern since they were detected in HTLV-endemic regions and in high-risk individuals in Brazil. The present study was conducted to extend and confirm these data. METHODS HTLV-1/2 and human immunodeficiency virus (HIV) infection status were identified in 1,984 sera for HBV and HCV viral load quantification - 1,290 samples from HBV-infected individuals (53.3% men, mean age: 47.1 years) and 694 samples from HCV-infected individuals (56.3% men, mean age: 50.1 years). HTLV-1/2 antibodies were detected by enzyme immunoassay, followed by western blotting and line immunoassay; HIV infection was detected by enzyme immunoassay. RESULTS HTLV-1/-2 infection was detected in 1.9% HBV-infected individuals (0.7% HTLV-1 and 1.2% HTLV-2) and in 4.0% (2.4% HTLV-1 and 1.6% HTLV-2) HCV-infected individuals; HIV infection was detected in 9.2% and 14.5%, respectively. Strong associations with HTLV and HIV, male sex, and older age were found in HBV/HTLV and HCV/HTLV-coinfected individuals (p<0.05). CONCLUSIONS HTLV-1 and HTLV-2 were confirmed to be prevalent in individuals with HBV and HCV in São Paulo; coinfected individuals deserve further clinical and laboratory investigation.

TREX1 531C>T Polymorphism is Associated with High Proviral Load Levels in HTLV-1-Infected Persons.

Human T-lymphotropic virus type 1 (HTLV-1) deregulates the immune system and cell cycle, resulting in loss of immune tolerance and disease, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Three prime repair exonuclease 1 (TREX1) maintains innate immune tolerance of the host and host-cell permissiveness to retroviral infections. TREX1 polymorphisms may influence the course of infection and autoimmune manifestations. The influence of TREX1 531C/T polymorphism was investigated in HTLV-1 infection and development of symptoms among 151 persons infected with HTLV-1 (32 HAM/TSP, 19 rheumatologic manifestations, two dermatitis, five more than one diagnosis, two probable HAM/TSP, and 91 asymptomatic individuals) and 100 uninfected persons in the control group. Polymorphism genotyping and proviral load quantification were performed by real-time polymerase chain reaction (PCR) and antinuclear antibodies (ANAs) were screened by an indirect immunofluorescence assay. No statistically significant difference was found in polymorphism genotype and allele frequencies between the infected and control groups. HAM/TSP patients showed higher frequency of TT genotype than asymptomatic persons (p = 0.0339). Proviral load was significantly higher among individuals with CT/TT genotypes and CC genotype carriers had lower proviral load and higher levels of proinflammatory cytokines. ANAs were present only in the HAM/TSP group. TREX1 531C>T polymorphism seems to be associated with TREX-1 regulation and HTLV-1 infection.

Noninvasive Detection of Antibodies to Human T-Cell Lymphotropic Virus Types 1 and 2 by Use of Oral Fluid

Human T-lymphotropic viruses type 1 and 2 (HTLV-1/2) are prevalent in endemic clusters globally, and HTLV-1 infects at least 5 to 10 million individuals. Infection can lead to inflammation in the spinal cord, resulting in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or adult T cell leukemia/lymphoma (ATL). Obtaining venous blood for serological screening, typically performed using enzyme immunoassays (EIAs), is invasive, sometimes socially unacceptable, and has restricted large-scale seroprevalence studies. Collecting oral fluid (OF) is a noninvasive alternative to venesection. In this study, an IgG antibody capture EIA was developed and validated to detect anti-HTLV-1/2 IgG in OF. OF and plasma specimens were obtained from seropositive HTLV-1/2-infected patients attending the National Centre for Human Retrovirology (n = 131) and from HTLV-1/2-uninfected individuals (n = 64). The assay showed good reproducibility and high diagnostic sensitivity (100%) and specificity (100%) using both OF and plasma. The Murex HTLV I+II commercial assay was evaluated and did not detect anti-HTLV-1/2 IgG in 14% (5/36) of OF specimens from seropositive donors. The reactivities of OF and plasma in the IgG capture correlated strongly (r = 0.9290) and were not significantly affected by delayed extraction when held between 3°C and 45°C for up to 7 days to simulate field testing. The use of OF serological screening for HTLV-1/2 infection could facilitate large-scale seroprevalence studies, enabling active surveillance of infection on a population level.

Novel Cellular Immunotherapy Using Allogeneic Vγ9/δ2-T Cells Gene-Modified to Express HTLV-1 P40Tax-Specific TCR for the Treatment of Adult T Cell Leukemia

Background: Adult T-cell leukemia/lymphoma (ATL) is a refractory peripheral T-cell malignancy caused by human T-lymphotropic virus type 1 (HTLV-1) infection. Although only allogeneic hematopoietic stem cell transplantation (allo-HSCT) displaying the graft-vs. ATL (GvATL) can bring durable remission, allo-HSCT is largely ineligible for newly diagnosed ATL patients due to disease aggressiveness and advanced age-related conditions. Thus, a novel treatment with safety and efficacy instead of allo-HSCT still remains an unmet need, and a cellular immunotherapy using TCR or CAR gene-modified immune cells exerting GvATL could be such an option. However, to generate those effector cells from autologous T cells of heavily pre-treated ATL patients faces many obstacles. To circumvent those hurdles, an employment of unconventional allogeneic Vγ9/δ2-T cells which are potentially free from the risk of GVHD could provide greater treatment opportunity for ATL patients due to highly extended donor availability. Taking above, here, we have newly devised an adoptive immunotherapy using a novel HTLV-1 p40Tax-specific TCR gene-modified allogeneic Vγ9/δ2 T cells against ATL. Methods: After written informed conscent, we firstly established novel HLA-A24 restricted TCR-α/β genes from HTLV-1 P40Tax301-309 (SFHSLHLLF)/HLA-A24 tetramer-positive peripheral CD8+T-lymphocytes of ATL patinets in durable remission using a single cell cloning method. Then, we confirmed that T cells gene-modified with these TCR-α/β genes exerted the epitope-specific and HLA-A24-restricted responses. Next, in order to achieve highly stable expression of this TCR-α/β heterodimer on gene-modified Vγ9/δ2-T cells, we newly developed a retroviral vector co-expressing TCR-α/β and CD8 α/β genes using self-cleaving P2A and E2A peptides. Using this vector, allogeneic Vγ9/δ2-T cells from healthy donors numerously expanded with high purity in our novel culture system were subjected to gene-transfer to express relevant TCR α/β complex. Thereafter, we asssessed target-reactive cytokine production and cytocidal activity mediated by those gene-modified allogeneic Vγ9/δ2-T cells both in vitro and in vivo. Finally, we additionally assessed a potential risk of GVHD using intravenous administration of another TCR gene-modified Vγ9/δ2 T-cells in vivo. Results: To start with PBMCs from healthy donors, allogeneic Vγ9/δ2-T cells were stably multiplied greater than thousandfold with a quite high purity (≥95%) using our novel bisphosphonate derivative PTA (tetrakis-pivaloyloxymethyl2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate) combined with both 25 ng/ml of IL-7 and IL-15 in culture for 8 to 10 days. The stable expression of introduced TCR α/β heterodimer on Vγ9/δ2-T cells were successfully achieved by co-expression of CD8 α/β molecule. Those gene-modified Vγ9/δ2-T cells successfully recognized target peptide (SFHSLHLLF) in an HLA-A24 restricted fashion, and similarly demonstrated a cytocidal activity both in vitro and in vivo against HLA-A24 positive HTLV-1 infected cell lines (TL-Su and ILT#Hod), but not HLA-A24-negtive/Tax-positive cell line ILT#37 or HLA-A24-positve/Tax-negative cell line ATN-1. Furthermore, intravenously administered those TCR gene-modified Vγ9/δ2-T cells quickly and durably eradicated luciferase-gene modified TL-Su cells, but not ATN-1 cells in xenografted immunodeficient (NOG) mice, examined by in vivo imaging system. Finally, infused HLA-A2 restricted and NY-ESO-1 specific TCR (G50) gene-modified Vγ9/δ2-T cells exerted durable antitumor activity without causing GVHD using NOG mice xenografted with HLA-A2 positive melanoma cell line cells (NW-MEL-38). Conclusions: Our preclinical observations here obviously demonstrated the potential utility of TCR-α/β gene-modified allogeneic Vγ9/δ2-T cells for the treatment of ATL without causing GVHD. Further studies regarding biological behaviors of HTLV-1 Tax specific TCR-α/β gene-modified allogeneic Vγ9/δ2-T cells following target recognition in vivo are warranted, however, based on these lines of evidence and currently conducting assessments using clinical samples, we are planning to launch a novel clinical trial, particularly focusing on the applicability of HLA partially matched relative donors, as the source of gene-modified allogeneic Vγ9/δ2-T cells, which could highly extend the donor availability. Disclosures Fujiwara: BrightPath Biotherapeutics, Co.,Ltd.: Other: member of the department endowed by BrightPath Bio. Okumura:BrightPath Biotherapeutics, Co.,Ltd.: Other: member of the department endowed by BrightPth Bio.. Miyahara:BirghtPath Biotherapeutics, Co., Ltd.: Other: member of the department endowed by BrightPath Bio.. Wan:BrightPath Biotherapeutics, Co., Ltd.: Other: member of the department endowed by BrightPath Bio.. Tawara:Astellas Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Shiku:BrightPath Biotherapeutics, Co., Ltd.: Other: Chair of the department endowed by BrightPath Bio..

Improved Overall Survival Among Newly Diagnosed Aggressive Adult T-Cell Leukemia/Lymphoma Patients Treated with Mogamulizumab Plus EPOCH Compared to Mogamulizumab Plus Vcap-AMP-Vecp

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare and quite refractory peripheral T-cell lymphoma. The human T-lymphotropic virus type 1 (HTLV-1) retrovirus causes ATLL. Tax protein produced by HTLV-1 has oncogenic activities, and its peptides can be recognized as tumor antigens by the host immune system. Therefore, some immunological approaches to treat ATLL are effective. Mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, and lenalidomide, an immunomodulator, have been recently approved for newly diagnosed and/or relapsed/refractory aggressive ATLL in Japan. However, to date, satisfactory treatment results have not been obtained with these drugs. Before approval of Moga and lenalidomide, VCAP-AMP-VECP (mLSG15) therapy was one of the standard combination chemotherapies for aggressive ATLL. A randomized phase II study comparing Moga plus mLSG15 and mLSG15 alone showed a higher %CR in Moga plus mLSG15 arm but no significant difference in overall survival (OS) between the two arms. In this study, we compared the outcomes of Moga plus EPOCH with those of Moga plus mLSG15. Methods: Aggressive ATLL patients, who were ineligible for hematopoietic stem cell transplantation (HSCT) and were newly diagnosed after June 2000 in our hospital, were retrospectively analyzed. Results: Table 1 summarizes the patient characteristics. Twenty-two patients were treated with Moga plus EPOCH, and 16 were treated with Moga plus mLSG15. There was no significant difference in gender and disease subtype between the groups. Moga-induced skin disorders, such as rash and erythema, were observed in 14 (64%) patients treated with Moga plus EPOCH group and 9 (56%) patients treated within Moga plus mLSG15; the difference was not significant. Figure 1 shows OS of both groups. There was no significant difference (P=0.3092), but a 30% risk reduction was observed in the Moga plus EPOCH group (hazard ratio [HR]: 0.6859, 95% confidence interval [CI]: 0.3165−1.430), though patients treated with Moga plus EPOCH were significantly older than those treated with Moga plus mLSG15 (Table 1). Figure 2 shows OS of patients with and without Moga-induced skin disorders in both groups. The OS of patients with skin disorders was significantly greater than that of those without skin disorders (P&lt;0.0001, HR: 0.2653, 95% CI: 0.05879−0.3628), as previously reported. Elevation of the Tax-specific cytotoxic T-lymphocytes (CTL) percentage was observed after occurrences of skin disorders in some patients. Representative data are shown in Figure 3. These data suggest that the combination chemotherapy regimen might be irrelevant for patients with Moga-induced skin disorders. Next, the OS of the Moga plus EPOCH group was compared with that of those treated with chemotherapy alone, such as mLSG15 and the CHOP-like regimen, as the historical control (Table 2). There was no statistical difference between the groups, but a 16% risk reduction was observed in the Moga plus EPOCH group (P=0.5885, HR: 0.8401, 95% CI: 0.4491−1.568) (Figure 4), though those treated with Moga plus EPOCH were significantly older than those treated with chemotherapy alone (Table 2). A 36% risk reduction in OS was observed in patients with Moga-induced skin disorders compared to those treated with chemotherapy alone (Figure 5). Conclusion: Improved OS was observed more frequently in the Moga plus EPOCH group than in the Moga plus mLSG15 group. However, to date, Moga plus chemotherapy has not shown a significant impact on OS for newly diagnosed aggressive ATLL patients in non-HSCT settings, except for patients with Moga-induced skin disorders. Elevation of the Tax-specific CTL percentage was observed in some patients with Moga-induced skin disorders. We previously reported in the 2014 ASH annual meeting that several aggressive ATLL patients, who obtained long-time survival using chemotherapy alone, had maintained Tax-specific CTLs for long periods. Therefore, it might be necessary to induce, up-regulate, and maintain ATLL-specific CTLs to obtain long-time survival. Moga is useful, but insufficient, for inducing such CTLs by suppressing regulatory T-cells. No effective method is available to activate an ATLL-specific cellular immune response. Further studies are urgently needed to establish effective methods for attaining ATLL-specific CTLs. Disclosures No relevant conflicts of interest to declare.

Cord Blood Transplantation with Non-TBI-RIC Regimen Using Fludarabine and Melphalan for Adult T-Cell Leukemia / Lymphoma

Adult T-cell leukemia/lymphoma (ATLL), which is a peripheral T-cell lymphoma related to human T-lymphotropic virus type I (HTLV-1), is known as a poor prognostic disease and its median age of onset is late 60s. Allogeneic hematopoietic stem cell transplantation is considered a treatment modality to contribute prolonging the survival in some population of patients. Although cord blood transplantation (CBT) widely practiced for hematological malignancies, a Japanese registry data suggested that 1 yr and 2 yrs overall survival (OS) after CBT in ATLL patients was only about 30% and 20%, respectively (Kato K, et al. 2014 BBMT). On the other hand, promising results were reported in the patients who were received CBT during their disease was controlled (Fukushima T, et al. 2013 IJH). Since it would be considered that CBT with non-TBI regimens, especially using reduced intensity conditioning (RIC), have a potential of engraftment failure compared to TBI regimen, it is less common conditioning regimen for CBT. Here we report a safety and an efficacy of CBT with non-TBI-RIC regimen using fludarabine (Flu) and melphalan (Mel) in 34 ATLL patients. We analyzed days from the beginning of systemic chemotherapy to transplantation, engraftment of neutrophil (EN), overall survival (OS), incidence of GVHD, non-relapse mortality (NRM) and disease-mortality (DRM), respectively. OS was defined as survival days from transplantation. OS were analyzed with logrank test. Cumulative incidence of EN and GVHD was considered with early death and NRM was considered with DRM as a competing risk. Incidence of GVHD, EN, NRM, and DRM was analyzed with Gray's method. Statistical significance defined P&lt;0.05. Statistical analysis was carried out using the EZR. Thirty-four patients (18 male, 16 female) were consecutively undergone CBT with non-TBI-RIC regimen using Flu 125 mg/m2 and Mel 140 mg/m2 between January, 2014 and August, 2018 at our institute where is located in HTLV-1-endemic area. Twenty-eight patients used tacrolimus 0.02 mg /kg/day (TAC) and methotrexate (MTX) 5 mg/m2 / day at day 1, 3, 6 after transplantation, 5 patients TAC and mycophenolate mofetil (MMF) 750-2000 mg/day and one patient TAC alone as a GVHD prophylaxis. Median age at CBT was 61 years (44-70) and 30 patients were diagnosed as acute type ATLL whereas 4 lymphoma type. Sixteen patients were status in CR and 18 non-CR at CBT. Median duration of observation was 839.5 days (370-1890) and median time to CBT from the beginning of systemic chemotherapy was 113 days (61-416). Cumulative incidence of EN was 91.2 % and median time to EN was 20 days (14-68). OS at 2 years after transplantation (2 yr OS) was 43.9 %. 2 yr OS in CR patients was 68.2 % whereas 22.2 % in non-CR. There is no statistical significance about OS in age, gender, and incidence of GVHD. Cumulative incidence of NRM at day 100 and DRM at 1 year after CBT was 26.5 % and 26.5 %, respectively. CBT with non-TBI-RIC regimen using Flu/Mel was safe based on the result of feasible incidence of EN and NRM after CBT. Since 43.9 % of 2 yr OS was relatively high rate compared to previous report of Japanese registry data, CBT with non-TBI-RIC regimen using Flu/Mel can be a promising treatment strategy for ATLL. Figure Disclosures Nakano: Novartis: Honoraria.

Prevalence and Molecular Epidemiology of Human T-Lymphotropic Virus Type 1 among Women Attending Antenatal Clinics in Sub-Saharan Africa: A Systematic Review and Meta-Analysis.

Human T-cell lymphotropic virus type 1 (HTLV-1) imposes a substantial disease burden in sub-Saharan Africa (SSA), which is arguably the world's largest endemic area for HTLV-1. Evidence that mother-to-child transmission persists as a major mode of transmission in SSA prompted us to estimate the pooled prevalence of HTLV-1 among pregnant women throughout the region. We systematically reviewed databases including EMBASE, MEDLINE, Web of Science, and the Cochrane Database of Systemic Reviews from their inception to November 2018. We selected studies with data on HTLV-1 prevalence among pregnant women in SSA. A random effect meta-analysis was conducted on all eligible data and heterogeneity was assessed through subgroup analyses. A total of 18 studies, covering 14,079 pregnant women, were selected. The evidence base was high to moderate in quality. The pooled prevalence, per 100 women, of the 18 studies that screened HTLV-1 was 1.67 (95% CI: 1.00-2.50), a figure that masks regional variations. In Western, Central, Southern, and Eastern Africa, the numbers were 2.34 (1.68-3.09), 2.00 (0.75-3.79), 0.30 (0.10-0.57), and 0.00 (0.00-0.21), respectively. The prevalence of HTLV-1 infection among pregnant women in SSA, especially in Western and Central Africa, strengthens the case for action to implement routine screening of pregnant women for HTLV-1. Rigorous studies using confirmatory testing and molecular analysis would characterize more accurately the prevalence of this infection, consolidate the evidence base, and further guide beneficial interventions.