Clinicopathological features of adult T-cell leukemia/lymphoma with T-follicular helper phenotype.

AIMS: T-follicular helper (TFH) cells are effector T-cells that are crucial for B-cell selection and differentiation. T-cell lymphomas derived from TFH cells have distinct characteristics. Additionally, in the World Health Organization (WHO) classification 5th edition, three lymphomas were introduced as independent disease entities with TFH cell origin. We aimed to investigate the clinicopathological features of adult T-cell leukemia/lymphoma (ATLL) with a TFH phenotype (TFHP). METHODS AND RESULTS: We performed TFH immunohistochemistry analysis of five biomarkers for the biopsy specimen, with TFHP being indicated by a positive result for more than two markers. Among 75 cases of ATLL, 37.3% of them showed TFHP. Compared with cases of ATLL without TFHP, cases of ATLL with TFHP showed higher C-reactive protein levels (p = 0.0219) and increased high endothelial venule proliferation (p = 0.024). However, there were no significant between-group differences in overall survival as well as other clinical and morphological findings. Furthermore, there was no significant between-group difference in TFH markers and FOXP3 expression. CONCLUSION: Some patients with ATLL may present a TFHP, which should not preclude the diagnosis of ATLL. Although presenting a TFHP does not affect prognosis, it is important to identify cases of ATLL with a TFHP since it may inform future treatment strategies.

Poor Outcome of Adult T-Cell Leukemia/Lymphoma with Current Available Therapy: An Experience of Two Centers.

INTRODUCTION: Adult T-cell leukemia lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1) infection. Despite its poor prognosis, there is no standard therapy for ATLL due to its low incidence and the disease affecting only endemic geographical clusters. METHODS: A retrospective evaluation of patients with the diagnosis of ATLL at Moffitt Cancer Center and Memorial Healthcare System was done to identify patients and disease characteristics along with the progression-free survival (PFS) and overall survival (OS) for the different therapies used. RESULTS: The 61 patients analyzed showed a median age of 58 with 82.5% of them being of African American descent. The acute variant contributed to the majority of cases (43.9%), followed by 36.8% presenting as a lymphoma variant. There was no statistical difference in the PFS (6.4 m, 3.1 m, 2.1 m; p = 0.23) or OS (14 m, 8.9 m, 18.5 m; p = 0.14) between cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), intensive chemotherapy regimens, and other modalities, respectively. However, the patients who had complete or partial remission with first-line therapy had better OS (15.9 m vs. 7.2 m; p = 0.004). CONCLUSIONS: The study highlighted the poor outcome of the current regimens and the lack of a unifying protocol for this vicious disease. The acute variants were treated with more intensive regimens, but there was no difference in the OS between the three major options of CHOP, intensified chemotherapy, and others. This underscores the need for more clinical trials to develop better outcomes.

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.

[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.

Small RNA Profiling in an HTLV-1-Infected Patient with Acute Adult T-Cell Leukemia-Lymphoma at Diagnosis and after Maintenance Therapy: A Case Study.

Small RNAs (sRNAs) are epigenetic regulators of essential biological processes associated with the development and progression of leukemias, including adult T-cell leukemia/lymphoma (ATLL) caused by human T-cell lymphotropic virus type 1 (HTLV-1), an oncogenic human retrovirus originally discovered in a patient with adult T-cell leukemia/lymphoma. Here, we describe the sRNA profile of a 30-year-old woman with ATLL at the time of diagnosis and after maintenance therapy with the aim of correlating expression levels with response to therapy.

The clinical impact of the ratio of C-reactive protein to albumin (CAR) in patients with acute- and lymphoma-type adult T-cell leukemia-lymphoma (ATL).

Recently, the ratio of C-reactive protein to albumin (CAR) is used as an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in solid tumors and hematological malignancy. However, no studies of the CAR have been performed in patients with adult T-cell leukemia-lymphoma (ATL). We retrospectively analyzed the clinical features and outcomes in 68 newly diagnosed acute- and lymphoma-type ATL [(acute-(n=42) or lymphoma-type (n=26)] patients in Miyazaki Prefecture from 2013 to 2017. Furthermore, we investigated correlations between pretreatment CAR levels and clinical features. The median age was 67 years (range, 44 - 87). Patients were initially treated by either palliative therapy (n=14) or chemotherapy [n=54; CHOP therapy (n=37)/ VCAP-AMP-VECP therapy (n=17)], and showed median survival durations of 0.5 months and 7.4 months, respectively. The factors affecting OS by multivariate analysis were age, BUN, and CAR. Importantly, we revealed that the high CAR group (optimal cut-off point; 0.553) was a significant indicator of worse OS by multivariate analysis (p< 0.001, HR; 5.46). The median survival of patients with a CAR< 0.553 was 8.37 months, while patients with a CAR>0.553 had a median survival of 3.94 months. The different clinical features between high CAR and low CAR groups were hypoproteinemia and the implementation of chemotherapy. Furthermore, in the chemotherapy group, but not the palliative therapy group, CAR was a significant prognostic marker. Our study indicated that CAR may be a new simple and significant independent prognostic marker in acute- and lymphoma-type ATL patients.

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.

Detection of HTLV-1 proviral DNA in cell-free DNA: Potential for non-invasive monitoring of Adult T cell leukaemia/lymphoma using liquid biopsy?

Introduction: Fragmented genomic DNA is constitutively released from dying cells into interstitial fluid in healthy tissue. In cancer, this so-called 'cell-free' DNA (cfDNA) released from dying malignant cells encodes cancer-associated mutations. Thus, minimally invasive sampling of cfDNA in blood plasma can be used to diagnose, characterise and longitudinally monitor solid tumours at remote sites in the body. ~5% of carriers of Human T cell leukaemia virus type 1 (HTLV-1) develop Adult T cell leukaemia/lymphoma (ATL), and a similar percentage develop an inflammatory CNS disease, HTLV-1 associated myelopathy (HAM). In both ATL and HAM, high frequencies of HTLV-1 infected cells are present in the affected tissue: each carrying an integrated DNA copy of the provirus. We hypothesised that turnover of infected cells results in the release of HTLV-1 proviruses in cfDNA, and that analysis of cfDNA from infected cells in HTLV-1 carriers might contain clinically useful information pertaining to inaccessible sites in the body- e.g. for early detection of primary or relapsing localised lymphoma type ATL. To evaluate the feasibility of this approach, we tested for HTLV-1 proviruses in blood plasma cfDNA. Methods: CfDNA (from blood plasma) and genomic DNA (gDNA, from peripheral blood mononuclear cells, PBMC) was isolated from blood from 6 uninfected controls, 24 asymptomatic carriers (AC), 21 patients with HAM and 25 patients with ATL. Proviral (HTLV-1 Tax) and human genomic DNA (the beta globin gene, HBB) targets were quantified by qPCR using primer pairs optimised for fragmented DNA. Results: Pure, high quality cfDNA was successfully extracted from blood plasma of all study participants. When compared with uninfected controls, HTLV-1 carriers had higher concentrations of cfDNA circulating in their blood plasma. Patients with ATL who were not in remission had the highest levels of blood plasma cfDNA in any group studied. HTLV-1 proviral DNA was detected in 60/70 samples obtained from HTLV-1 carriers. The proviral load (percentage of cells carrying proviruses) was approximately tenfold lower in plasma cfDNA than in PBMC genomic DNA, and there was a strong correlation between the proviral load in cfDNA and PBMC genomic DNA in HTLV-1 carriers that did not have ATL. cfDNA samples in which proviruses were undetectable also had very low proviral load in PBMC genomic DNA. Finally, detection of proviruses in cfDNA of patients with ATL was predictive of clinical status: patients with evolving disease had higher than expected total amount of proviruses detectable in plasma cfDNA. Discussion: We demonstrated that (1) HTLV-1 infection is associated with increased levels of blood plasma cfDNA, (2) proviral DNA is released into blood plasma cfDNA in HTLV-1 carriers and (3) proviral burden in cfDNA correlates with clinical status, raising the possibility of developing assays of cfDNA for clinical use in HTLV-1 carriers.

Epidemiological Features and Outcomes of HTLV-1 Carriers Diagnosed With Cancer: A Retrospective Cohort Study in an Endemic Country.

PURPOSE: Human T-lymphotropic virus type 1 (HTLV-1) is an endemic virus in Latin America that is directly linked to adult T-cell leukemia/lymphoma (ATL). Previous studies have suggested an oncogenic role of HTLV-1 in non-ATL neoplasms and have found higher mortality in HTLV-1 carriers without ATL. METHODS: In this retrospective cohort study, HTLV-1 carriers were identified through screening at a tertiary cancer center between 2006 and 2019. We compared the overall survival (OS) outcomes of patients with ATL with those with other solid or hematologic malignancies by sex stratification. RESULTS: We identified 1,934 HTLV-1 carriers diagnosed with cancer. The median age at diagnosis was 62 (range 20-114) years, 76% were female, 60% had no or elementary school education, and 50% were born in the Andean highlands. The most common non-ATL neoplasm was cervical cancer (50%) among females and non-ATL non-Hodgkin lymphoma (26%) among males. With a median follow-up of 66 months, the 5-year OS of HTLV-1 carriers with non-ATL neoplasms (26%-47% for females and 22%-34% for males) was inferior to those reported in the general population. As expected, patients with ATL had a worse prognosis (5-year OS: 10% for females and 8% for males). CONCLUSION: HTLV-1 carriers with cancer were middle age and from underprivileged settings, suggesting an undetected transmission among vulnerable populations, especially females. Survival estimates of HTLV-1 carriers with non-ATL neoplasms were lower than the regional outcomes. Future research should ascertain how the biology of HTLV-1 and health care disparities affect the outcomes of HTLV-1 carriers, as well as determine the burden of HTLV-1 infection in the cancer population to recommend screening in the outpatient setting of endemic regions.

Human T-cell Leukemia Virus Type 1 (HTLV-1)-induced Uveitis.

Human T-cell leukemia virus type 1 (HTLV-1) is a human retrovirus that causes T-cell malignant diseases (adult T-cell leukemia/lymphoma) and HTLV-1-related non-malignant inflammatory diseases, such as HTLV-1 uveitis. Although the symptoms and signs of HTLV-1 uveitis are nonspecific, intermediate uveitis with various degrees of vitreous opacity is the most common clinical presentation. It can occur in one or both eyes and its onset is acute or subacute. Intraocular inflammation can be managed with topical and/or systemic corticosteroids; however, recurrence of uveitis is common. The visual prognosis is generally favorable, but a certain proportion of patients have a poor visual prognosis. Systemic complications of patients with HTLV-1 uveitis include Graves' disease and HTLV-1-associated myelopathy/tropical spastic paraparesis. This review describes the clinical characteristics, diagnosis, ocular manifestations, management, and immunopathogenic mechanisms of HTLV-1 uveitis.

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.

A decrease in newly diagnosed patients with adult T-cell leukemia/lymphoma in Kagoshima, a highly endemic area of HTLV-1 in southwestern Japan.

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type-I (HTLV-1). This study investigated whether the number of newly diagnosed patients with ATL is decreasing in the background of a declining number of individuals infected by HTLV-1 in Kagoshima, Japan, one of the most endemic areas of HTLV-1 in the world. We retrospectively analyzed the number of newly diagnosed patients with ATL between January 2001 and December 2021 in three major hospitals. The number of newly diagnosed patients with B-cell non-Hodgkin lymphoma (B-NHL) in the same period was examined as an internal control. One thousand eighteen and 2,029 patients with ATL and B-NHL were registered, respectively. The age-adjusted incidence of ATL steadily increased between 2001 and 2012, whereas that between 2013 and 2021 decreased. Despite the limitation of its retrospective nature, this is the first report indicating a decrease in ATL patients in Japan.

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.

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.

The importance of the clinical classification of adult T-cell leukemia/lymphoma (ATLL) in the prognosis.

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL), a peripheral T-cell leukemia/lymphoma associated with the human T-cell lymphotropic virus type-1 (HTLV-1), has been classified following the clinical forms defined by Shimoyama in 1991. A suggestion to modify Shimoyama's classification was proposed in 2007 to differentiate within the smoldering patients those who presented nodules or tumors in the skin without lung involvement, which was named the primary cutaneous tumoral (PCT) form of ATLL. In the present study, according to their clinicopathological characteristics, we estimated the mortality rates of 143 ATLL patients from Bahia, Brazil. We also evaluated the importance of classifying PCT/ATLL separately from the smoldering type on disease prognosis. METHODOLOGY/PRINCIPAL FINDINGS: Diagnosis of ATLL was established based on a positive serology for HTLV-1, histopathological and/or cytological diagnosis of peripheral T-cell leukemia/lymphoma. Patients were clinically grouped according to Shimoyama's classification, considering PCT variants separately from the smoldering cases. Bivariate and multivariable survival analyses were applied to identify factors associated with disease prognosis. Significant differences in the median survival time were observed between the clinical types, with the smoldering type presenting the longest median survival (109 months) compared to the other forms (<50 months); the median survival for PCT/ATLL was 20 months. Multivariable analysis confirmed that ATLL clinical types were associated with survival, with a better prognosis for patients with the smoldering and chronic types. Furthermore, skin involvement was related to a worse outcome in the multivariable analysis, regardless of the clinical form and presence of lymphadenopathy. CONCLUSIONS/SIGNIFICANCE: Our results reinforce the importance of considering the PCT/ATLL separately from the smoldering type when classifying ATLL to better define prognosis and treatment, given the significant difference in the survival of patients between the smoldering form and PCT/ATLL. Skin involvement should also be considered an independent prognostic factor in patients with ATLL.

HTLV-1-related adult T-cell leukemia/lymphoma: insights in early detection and management.

PURPOSE OF REVIEW: Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature T-cell malignancy that arises in approximately 5% of carriers of human T-lymphotropic virus type 1 (HTLV-1), but this risk is not random among carriers. We describe recent advance in pathogenesis, risk factors and for early detection of ATL. RECENT FINDINGS: Unraveling ATL molecular genetics has shed light on pathogenesis and provides insights into novel therapeutic targets. Moreover, an important step in improving outcomes is identifying asymptomatic carriers who are at high risk of progression to ATL, which has traditionally relied on quantifying the proviral load (PVL). This can be done by quantifying oligoclonality- and in particular the expanded clone- with molecular and flow cytometric techniques, that can be applied to a clinical setting. Studies using these methods have shown that carriers with oligoclonal populations are at an increased risk of transformation, beyond that that predicted by PVL alone. SUMMARY: There is an urgent unmet need for developing novel therapies in ATL in order to improve survival. Recent advances in the molecular and epigenetic landscape of ATL, and the early detection of disease offer the potential to intervene early, before disease becomes aggressive, and to offer tailored therapeutic strategies.

Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma.

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.