[Ruptured mycotic cerebral aneurysm in an adult T-cell leukemia/lymphoma patient undergoing allogeneic stem cell transplantation].

A 63-year-old man with adult T-cell leukemia-lymphoma underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. On day 17 after transplantation, chest computed tomography (CT) showed nodules in the lower lobes of both lungs, and invasive pulmonary aspergillosis (IPA) was suspected. Treatment with liposomal amphotericin B was started, and improvement of infectious lesions was confirmed with CT on day 28. The antifungal agent was changed to voriconazole on day 52 because of progressive renal dysfunction. Disorders of consciousness and paralysis of the left upper and lower extremities developed on day 61. Brain CT showed subcortical hemorrhage in the right parietal and occipital lobes, and the patient died on day 62. An autopsy revealed filamentous fungi, suspected to be Aspergillus, in the pulmonary nodules and a ruptured cerebral aneurysm. Although IPA occurs in 10% of transplant recipients, vigilant monitoring for mycotic cerebral aneurysms is required to prevent hematogenous dissemination of Aspergillus, which is associated with a high mortality rate.

Stem cell therapy for HTLV-1 induced adult T-cell leukemia/lymphoma (ATLL): A comprehensive review.

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive form of cancer associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. The emerging field of stem cell therapies for ATLL is discussed, highlighting the potential of hematopoietic stem cell transplantation (HSCT) and genetically modified stem cells. HSCT aims to eradicate malignant T-cells and restore a functional immune system through the infusion of healthy donor stem cells. Genetically modified stem cells show promise in enhancing their ability to target and eliminate ATLL cells. The article presents insights from preclinical studies and limited clinical trials, emphasizing the need for further research to establish the safety, efficacy, and long-term outcomes of stem cell therapies for ATLL and challenges associated with these innovative approaches are also explored. Overall, stem cell therapies hold significant potential in revolutionizing ATLL treatment, and ongoing clinical trials aim to determine their benefits in larger patient populations.

Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia-Lymphoma.

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.

The Novel Link between Gene Expression Profiles of Adult T-Cell Leukemia/Lymphoma Patients' Peripheral Blood Lymphocytes and Ferroptosis Susceptibility.

Ferroptosis, a regulated cell death dependent on iron, has garnered attention as a potential broad-spectrum anticancer approach in leukemia research. However, there has been limited ferroptosis research on ATL, an aggressive T-cell malignancy caused by HTLV-1 infection. Our study employs bioinformatic analysis, utilizing dataset GSE33615, to identify 46 ferroptosis-related DEGs and 26 autophagy-related DEGs in ATL cells. These DEGs are associated with various cellular responses, chemical stress, and iron-related pathways. Autophagy-related DEGs are linked to autophagy, apoptosis, NOD-like receptor signaling, TNF signaling, and the insulin resistance pathway. PPI network analysis revealed 10 hub genes and related biomolecules. Moreover, we predicted crucial miRNAs, transcription factors, and potential pharmacological compounds. We also screened the top 20 medications based on upregulated DEGs. In summary, our study establishes an innovative link between ATL treatment and ferroptosis, offering promising avenues for novel therapeutic strategies in ATL.

[Adult T-cell leukemia/lymphoma].

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.

Therapeutic approaches for HTLV-1-associated adult T-cell leukemia/lymphoma: a comprehensive review.

Adult T-cell leukemia/lymphoma (ATLL), an infrequent malignancy resultant from human T-cell lymphotropic virus type I (HTLV-1), exhibits a spectrum of phenotypes, encompassing acute, smoldering, lymphomatous, and chronic variants, each bearing distinct clinical presentations. The preponderant acute manifestation is characterized by hypercalcemia, systemic manifestations, organomegaly, and dermatological eruptions. Conversely, the chronic phenotype is typified by lymphocytosis and/or cutaneous eruptions, while smoldering ATLL assumes an asymptomatic course. Immunocompromise afflicts ATLL patients, heightening their vulnerability to opportunistic infections that frequently intricately intertwine with disease progression. Therefore, an early diagnosis is crucial to manage the disease appropriately. While conventional chemotherapeutic regimens have shown limited success, especially in acute and lymphoma types, recent studies suggest that allogeneic stem cell transplantation might enhance treatment results because it has shown promising outcomes in some patients. Novel therapeutics, such as interferon and monoclonal antibodies, have also shown promise, but more research is needed to confirm their efficacy. Moreover, the identification of biomarkers for ATLL and genetic changes in HTLV-1 infected cells has led to the development of targeted therapies that have shown remarkable success in clinical trials. These targeted therapies have the potential to offer a more personalized approach to the treatment of ATLL. The aim of our review is to elaborate on conventional and novel therapies and the efficiency of mentioned treatments.

[Tax-targeted dendritic cell vaccine therapy for long-term remission of adult T-cell leukemia-lymphoma].

Adult T-cell leukemia-lymphoma (ATL) is a highly aggressive peripheral T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1) infection occurring in approximately 5% of patients after prolonged latent period. ATL relapses within a short period despite its transient response to multiagent chemotherapy and the prognosis is extremely poor due to anticancer drug resistance and immunodeficiency. Although novel agents with different mechanisms, such as molecular targeted agents, have improved the prognosis, the number of cured patients remains limited. Hematopoietic stem cell transplantation resulted in long-term remission, whereas its indication is limited due to treatment-related mortality. As most ATL patients are of advanced age, development of a lesser toxic treatment is necessary. Therefore, we developed a novel therapeutic dendritic cell vaccine targeting the HTLV-1 Tax antigen. The safety profile has been confirmed in a pilot and phase I clinical studies, and a promising long-term clinical efficacy has also been obtained. This novel vaccine is a noninvasive, long-lasting therapy for ATL and can potentially be extended to different applications for low-grade ATL and high-risk HTLV-1 carriers.

[Adult T-cell leukemia/lymphoma: progress in understanding of pathogenesis and treatment].

Adult T-cell leukemia/lymphoma (ATL) is an exceedingly refractory peripheral T-cell lymphoma. Despite the approval of a few new drugs for managing patients with newly diagnosed or relapsed/refractory ATL in recent years, the prognosis has yet to be substantially ameliorated. This study focuses on recent topics on the development of innovative therapies and the identification of prognostic indicators, considering the recent elucidation of the pathogenesisof ATL. Specifically, this study also delineates the advancements in developing novel EZH1/2 inhibitors and comprehensive genetic analysis; the molecular pathogenesis determined through comprehensive gene knockdown and knockout techniques, with its potential as a therapeutic target; the latest discoveries from the analysis of super-enhancer regions; and the prognostic factors extracted from comprehensive genetic analysis.

Gene expression and TCR amino acid sequences selected by HLA-A02:01-restricted CTLs specific to HTLV-1 in ATL patients.

Adult T-cell leukaemia/lymphoma (ATL) is an aggressive malignancy of peripheral T cells caused by human T-cell lymphotropic virus type-1 (HTLV-1). Tax is the most important regulatory protein for HTLV-1. We aimed to reveal a unique amino acid sequence (AA) of complementarity-determining region 3 (CDR3) of the T-cell receptor (TCR)ß and TCRα chains of HLA-A*02:01-restricted Tax11-19 -specific cytotoxic T cells (Tax-CTLs). The gene expression profiles (GEP) of Tax-CTLs were assessed by the next-generation sequence (NGS) method with SMARTer technology. Tax-CTLs seemed to be oligoclonal, and their gene compositions were skewed. The unique motifs of 'DSWGK' in TCRα and 'LAG' in TCRß at CDR3 were observed in almost all patients. Tax-CTL clones harbouring the 'LAG' motif with BV28 had a higher binding score than those without either of them, besides a higher binding score associated with longer survival. Tax-CTLs established from a single cell showed killing activities against Tax-peptide-pulsed HLA-A2+ T2 cell lines. GEP of Tax-CTLs revealed that genes associated with immune response activity were well preserved in long-term survivors with stable status. These methods and results can help us better understand immunity against ATL, and should contribute to future studies on the clinical application of adoptive T-cell therapies.

Treatment of Adult T-Cell Leukemia/Lymphoma: Established Paradigms and Emerging Directions.

OPINION STATEMENT: 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.

Impact of HLA-mismatched unrelated transplantation in patients with adult T-cell leukemia/lymphoma.

This Japanese nationwide retrospective study investigated the impact of HLA-mismatched unrelated transplantation for adult T-cell leukemia-lymphoma (ATL) patients who received transplantation between 2000 and 2018. We compared 6/6 antigen-matched related donor (MRD), 8/8 allele-matched unrelated donor (8/8MUD), and 1 allele-mismatched unrelated donor (7/8MMUD) in the graft-versus-host direction. We included 1191 patients; 449 (37.7%) were in the MRD group, 466 (39.1%) in the 8/8MUD group, and 276 (23.7%) in the 7/8MMUD group. In the 7/8MMUD group, 97.5% of patients received bone marrow transplantation, and no patients received post-transplant cyclophosphamide. The cumulative incidences of non-relapse mortality (NRM) and relapse at 4 years, and the probabilities of overall survival at 4 years in the MRD group were 24.7%, 44.4%, 37.5%, in the 8/8MUD group were 27.2%, 38.2%, and 37.9%, and in the 7/8MMUD group were 34.0%, 34.4%, and 35.3%, respectively. The 7/8MMUD group had a higher risk of NRM (hazard ratio (HR) 1.50 [95% CI, 1.13-1.98; P = 0.005]) and a lower risk of relapse (HR 0.68 [95% CI, 0.53-0.87; P = 0.003]) than the MRD group. The donor type was not a significant risk factor for overall mortality. These data suggest that 7/8MMUD is an acceptable alternative donor when an HLA-matched donor is unavailable.

[Clinical Analysis of SET-NUP214 Fusion Gene Positive Patients with Acute Leukemia].

OBJECTIVE: To analyze the characteristics and prognosis of acute leukemia(AL) with SET-NUP214 fusion gene. METHODS: The clinical data of 17 patients over 14 years old newly diagnosed with SET-NUP214 positive AL admitted in Institute of Hematology and Blood Diseases Hospital from August 2017 to May 2021 were analyzed retrospectively. RESULTS: Among the 17 SET-NUP214 positive patients, 13 cases were diagnosed as T-ALL (ETP 3 cases, Pro-T-ALL 6 cases, Pre-T-ALL 3 cases, Medullary-T-ALL 1 case), AML 3 cases (2 cases M5, 1 case M0) and ALAL 1 case. Thirteen patients presented extramedullary infiltration at initial diagnosis. All 17 patients received treatment, and a total of 16 cases achieved complete remission (CR), including 12 cases in patients with T-ALL. The total median OS and RFS time were 23 (3-50) months and 21 (0-48) months, respectively. Eleven patients received allogeneic hematopoietic stem cell transplantation(allo-HSCT), with median OS time of 37.5 (5-50) months and median RFS time of 29.5 (5-48) months. The median OS time of 6 patients in chemotherapy-only group was 10.5 (3-41) months, and median RFS time of 6.5 (3-39) months. The OS and RFS of patients with transplantation group were better than those of chemotherapy-only group (P=0.038). Among the 4 patients who relapsed or refractory after allo-HSCT, the SET-NUP214 fusion gene did not turn negative before transplantation. While, in the group of 7 patients who have not relapsed after allo-HSCT till now, the SET-NUP214 fusion gene expression of 5 patients turned negative before transplantation and other 2 of them were still positive. CONCLUSION: The fusion site of SET-NUP214 fusion gene is relatively fixed in AL patients, often accompanied by extramedullary infiltration. The chemotherapy effect of this disease is poor, and allo-HSCT may improve its prognosis.

CAR-iNKT cells targeting clonal TCRVß chains as a precise strategy to treat T cell lymphoma.

Introduction: Most T cell receptor (TCR)Vß chain-expressing T cell lymphomas (TCL) including those caused by Human T cell leukaemia virus type-1 (HTLV-1) have poor prognosis. We hypothesised that chimeric antigen receptor (CAR)-mediated targeting of the clonal, lymphoma-associated TCRß chains would comprise an effective cell therapy for TCL that would minimally impact the physiological TCR repertoire. Methods: As proof of concept, we generated CAR constructs to target four TCRVß subunits. Efficacy of the CAR constructs was tested using conventional T cells as effectors (CAR-T). Since invariant NKT (iNKT) cell do not incite acute graft-versus-host disease and are suitable for 'off-the-shelf' immunotherapy, we generated anti-TCRVß CAR-iNKT cells. Results: We show that anti-TCRVß CAR-T cells selectively kill their cognate tumour targets while leaving >90% of the physiological TCR repertoire intact. CAR-iNKT cells inhibited the growth of TCL in vivo, and were also selectively active against malignant cells from Adult T cell leukaemia/lymphoma patients without activating expression of HTLV-1. Discussion: Thus we provide proof-of-concept for effective and selective anti-TCRVß CAR-T and -iNKT cell-based therapy of TCL with the latter providing the option for 'off-the-shelf' immunotherapy.

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma.

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).

Prospects of early therapeutic interventions for indolent adult T-cell leukemia/lymphoma based on the chronic lymphocytic leukemia progression model.

Adult T-cell leukemia/lymphoma (ATLL) has aggressive clinical behaviors, and improving its prognosis is a great challenge. A disease progression model from asymptomatic human T-cell leukemia virus type 1 carrier to aggressive-type ATLL has been proposed, and indolent ATLL comprising a smoldering or favorable chronic type is located at the midpoint. Even the most favorable smoldering type has a 4-year overall survival rate of <60%. Although watchful waiting is pervasive in patients with indolent ATLL, early therapeutic intervention is discussed among hematologists. Indolent ATLL was once termed T-cell-derived chronic lymphocytic leukemia (CLL). Unlike indolent ATLL, several molecular-targeted agents at the initial treatment have dramatically improved CLL prognosis. Recent studies on CLL have revealed a similar progression model involving premalignant monoclonal B-cell lymphocytosis (MBL). In particular, individuals with high-count MBL have an increased lymphoma risk. Considering the unsatisfactory long-term prognosis of indolent ATLL, further treatment strategies, including precision medicine, are warranted.

Prognostic indices for peripheral T-cell lymphoma - not otherwise specified and adult T-cell leukemia/lymphoma: From past to future.

Several prognostic indices have been reported for peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL). The clinical features and prognosis of PTCL differ in a specified pathological diagnosis, whereas those of ATL are more diverse, even in the same clinical subtypes of acute, lymphoma, chronic, and smoldering. The establishment of a prognostic index is important not only for a risk-stratified treatment approach, but also for the preliminary evaluation of therapeutic findings by novel modalities, particularly in rare and aggressive diseases such as ATL. Five prognostic indices for PTCL-not otherwise specified and 6 prognostic indices for ATL are discussed herein. Recent advances in molecular analyses have facilitated prognostication using molecular profiles. In addition to the external validation of these prognostic indices, which are mostly established by clinical information, the development of novel indices by incorporating molecular profiles is warranted to improve the outcomes of patients through the selection of optimal treatments.

Primary Effusion Lymphoma-like ATL Developing during Hemodialysis.

We herein report a patient with primary effusion lymphoma-like adult T-cell leukemia/lymphoma (PEL-like ATL) that developed during hemodialysis. A 77-year-old man developed a fever and ascites. Elevated levels of lactate dehydrogenase (LDH), calcium and soluble interleukin-2 receptor (sIL-2R) along with antibodies to human T-cell leukemia virus type 1 (HTLV-1) were seen in his blood. Lymphoma cells in ascites were positive for HTLV-1 proviral DNA, but there were no neoplastic cells in peripheral blood or bone marrow and no lymphadenopathy. He was therefore diagnosed with PEL-like ATL, acute-type. After administration of brentuximab vedotin, his serum LDH, sIL-2R and atypical cells in ascites cytology decreased. The development of novel effective molecular-targeted therapies is warranted.

Validation of the iATL-PI prognostic index in therapeutic decision-making for patients with smoldering and chronic ATL: a multicenter study.

Adult T cell leukemia-lymphoma (ATL) is clinically heterogeneous and is classified into four subtypes: acute, lymphoma, chronic, and smoldering. Recently, a new prognostic index based on the value of soluble interleukin-2 receptor, denoted the "iATL-PI," has been proposed for patients with smoldering and chronic ATL. To evaluate the effectiveness of the iATL-PI, we re-analyzed our previously published data on 176 patients with smoldering or chronic ATL (76 smoldering, 100 chronic) diagnosed between 2010 and 2011, as well data from the subsequent follow-up study on prognosis between 2016 and 2017. The proportions for the low-, intermediate-, and high-risk iATL-PI groups at the time of ATL diagnosis were 44.7%, 48.7%, and 5% for smoldering ATL; 6.3%, 71.9%, and 21.9% for favorable chronic ATL; and 5.9%, 27.9%, and 66.2% for unfavorable chronic ATL, respectively. The survival of patients with smoldering or chronic ATL as a whole was significantly stratified according to the three iATL-PI groups. Most patients with unfavorable chronic ATL in the low iATL-PI risk group had indolent clinical courses. Our results showed that iATL may become a useful tool to predict the prognosis of smoldering and chronic ATL, which have diverse clinical courses.