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The indolent adult T-cell leukemia-lymphoma prognostic index (iATL-PI) uses soluble interleukin-2 receptor (sIL-2R) levels of 1,000 and 6,000 U/mL as a cut-off. The disadvantage of the iATL-PI is that approximately half of the patients are classified as intermediate risk (1,000 ≤ sIL-2R < 6,000). Here, we aimed to develop a novel prognostic model for indolent ATL using a prospectively registered database. We identified 375 patients with indolent ATL. Median age was 61 years. The median follow-up of surviving patients was approximately 62 months. In multivariate analysis for overall survival (OS), sIL-2R level (as log(sIL-2R), HR 4.58), male sex (HR 1.41) and LDH > ULN (HR 1.68) were independent prognostic factors. The best cut-off value for sIL-2R to predict OS was 2,870 U/mL. Including the cut-off of 3,000 U/mL in the original iATL-PI, the probabilities of 5-year OS were 88.9% in the low group (sIL-2R < 1,000), 67.5% in the low-intermediate group (1,000 ≤ sIL-2R < 3,000), 34.0% in the high-intermediate group (3,000 ≤ sIL-2R < 6,000) and 17.0% in the high group (sIL-2R ≥ 6,000). The c-index for predicting OS was higher with the modified iATL-PI than with the original iATL-PI (0.749 vs. 0.725). The addition of sex and LDH levels did not improve the c-index. In conclusion, we developed a novel prognostic index of indolent ATL.

Adult T‐cell leukemia/lymphoma (ATL) is a mature T‐cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983‐1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010‐2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow‐up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016‐2017. Of 770 evaluable patients, 391 (50.8%) had acute‐type, 192 (24.9%) had lymphoma‐type, 106 (13.8%) had chronic‐type, and 81 (10.5%) had smoldering‐type ATL. The initial therapy regimens used for acute/lymphoma‐type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP‐AMP‐VECP)‐like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)‐like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma‐type ATL patients. The 4‐year survival rates (the median survival time, days) for acute‐, lymphoma‐, unfavorable chronic‐, favorable chronic‐, and smoldering‐type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4‐year survival rates for acute‐ and lymphoma‐type ATL improved compared with those reported in 1991, but those for chronic‐ and smoldering‐type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan. The survival curve shows that the prognoses of patients with acute and lymphoma‐type ATL in Japan have improved modestly, but those of patients with chronic and smoldering‐type ATL have not improved.

Adult T-cell leukaemia-lymphoma (ATL) is a malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1), and its prognosis is poor. There are an estimated 5 million to 20 million HTLV-1 infected individuals worldwide; their lifetime risk of developing ATL is 3–5%, and high HTLV-1 proviral loads have been shown to be an independent risk factor. Recent advances in the treatment of ATL are the introduction of treatment targeted against CC chemokine receptor 4 (CCR4), which is abundantly expressed on most ATL cells, and allogeneic haemopoietic stem-cell transplantation for aggressive ATL. Promising outcomes are also reported with early intervention for indolent ATL with interferon α and zidovudine. Clinical trials should incorporate a validated prognostic index to assess the results, because of the difficulties associated with undertaking large-scale trials and significant diversity of clinical features with ATL, even in the same clinical subtypes (acute, lymphoma, chronic, and smoldering).

Genetic alterations in adult T‐cell leukemia/lymphoma (ATLL), a T‐cell malignancy associated with HTLV‐1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next‐generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV‐1 tax subgroup‐A (HTLV‐1‐taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV‐1‐taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF‐ĸB (eg, PRKCB, PLCG1, and CARD11) and T‐cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome‐associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV‐1‐taxB, HTLV‐1‐taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics. Targeted next‐generation sequencing and single nucleotide polymorphism array were applied to analyze aggressive adult T‐cell leukemia/lymphoma in Okinawa, which were not included in prior genomic studies. Our results showed that HTLV‐1 tax subgroup‐A was associated with high alteration frequencies in GATA3 and RHOA. Clinically, biallelic alterations, not heterozygous deletions or mutations, of PRDM1 were significantly associated with poor prognosis.

Although adult T-cell leukemia/lymphoma (ATL) has a higher burden in Latin America compared to North American or European countries, few studies have described the outcomes of this disease. We estimated the hospital-based prevalence and overall survival (OS) of ATL. We conducted a cohort study among patients aged ≥ 18 years with pathologically diagnosed mature T-cell lymphoma across 11 Latin American countries from 2000 to 2023 by pooling data from 3 hospital-based registries. We used the Kaplan-Meier method to estimate survival outcomes. Among 1963 patients with mature T-cell lymphoma, the pooled prevalence of ATL was 17 % (n = 329; 95 % confidence interval [CI]=15–18 %), with the highest observed in Peru (n = 158; 38 %, 95 % CI=33–43 %) and Colombia (n = 17; 29 %, 95 % CI=18–41 %). Over time, ATL cases only increased significantly in Peru, from 14 % in 2000–2004 to 58 % in 2019–2023 (Ptrend<0.001). With a median follow-up of 37 months (95 % CI=30–54 months), the 3-year OS of ATL was 25 % (95 % CI=20–32 %), and the median OS was 9 months (95 % CI=8–12 months). OS did not differ across countries (range 19–47 %, P = 0.210). Patients with lymphomatous ATL had worse outcomes than those with PTCL-NOS only in Peru (Pheterogeneity=0.029). Our findings indicate a higher ATL prevalence in Latin America than previously reported in North America or Europe, likely due to differences in HTLV-1 endemicity and diagnostic practices. The similar and poor survival rates across countries underscore the need for targeted interventions to improve patient outcomes. We propose expert-based research priorities and suggest further epidemiological validation studies. •ATL prevalence in Latin America is likely higher than in other regions.•Survival rates for ATL patients remain poor across countries.•Lack of HTLV screening may lead to misdiagnosis of ATL as PTCL-NOS.•Population- based validation studies and expert-based research priorities and are needed to improve outcomes•Collaborative capacity-building will accelerate discovery and enhance ATL-related health outcomes globally

The prognosis of adult T-cell leukemia/lymphoma (ATL) with primary central nervous system (CNS) involvement has been unclear since the advent of new therapies. Recently, we have shown that flow cytometric CD7/CADM1 analysis of CD4 + cells (HAS-Flow) is useful to detect ATL cells that are not morphologically diagnosed as ATL cells. We investigated the role of CNS involvement in ATL using cytology and HAS-Flow by analyzing cerebrospinal fluid (CSF) from 73 aggressive ATL cases. Based on the findings in CSF, the study subjects were classified into CNS + (cytologically malignant, n  = 18), CNS- (cytologically non-malignant and ATL cell population negative in HAS-Flow, n  = 44), and CNS-Micro (cytologically non-malignant and ATL cell population positive in HAS-Flow, n  = 11) groups. As expected, the CNS + group had a shorter overall survival than the CNS- groups ( P  < 0.001). However, the CNS-Micro group showed no adverse impact on overall survival compared to the CNS- group ( P  = 0.506), even without additional CNS-targeted treatments. HAS-Flow also demonstrated clinical utility in the diagnosis of CSF lesions in ATL patients with cerebral white matter lesions and in the detection of ATL cells on post-treatment CSF examination in patients with CNS involvement. Our study demonstrates that ATL with CNS involvement have a poor prognosis and that CSF HAS-Flow is useful to assist in the diagnosis of suspected CNS involvement and to detect ATL cells with high sensitivity after treatment.

Recent advances in treatment for adult T‐cell leukemia‐lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally because of advances in chemotherapy, further prolongation of survival might be difficult with conventional chemotherapy alone. Promising results have been reported for antiviral therapy using zidovudine and interferon‐α, and, indeed, antiviral therapy is currently the standard treatment for patients with ATL in western countries. Remarkably, the 5‐year OS rates are 100% for both the smoldering‐type and chronic‐type ATL. Recently, treatments for ATL have included allogeneic hematopoietic stem cell transplantation and molecular targeted therapies. Furthermore, the anti‐CCR4 monoclonal antibody mogamulizumab has been shown to have marked cytotoxic effects on ATL cells, especially in the leukemic type of ATL. In the lymphoma type of ATL, the response rate may be improved by combining mogamulizumab with chemotherapy. It should be recognized that prevention of infection from carriers of human T‐cell leukemia virus type‐I and transfer of the virus from mother to infant are crucial issues for the eradication of ATL. The prognosis of ATL is very poor by conventional chemotherapies. On the other hands, antiviral therapy of zidovudine and interferon‐α is currently the gold standard for patients with leukemic type ATL in Western countries although it is not confirmed yet in Japan. By various attempts including allogeneic hematopoietic stem cell transplantation and molecular target therapies, around one‐third of aggressive type ATL cases can be now cured.

Adult T‐cell leukemia/lymphoma (ATLL) is a mature T‐cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK‐STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression‐free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL. In the present study, we investigated the potential role of the STAT3 pathway in adult T‐cell leukemia/lymphoma (ATLL). We carried out immunohistochemistry for activated/phosphorylated STAT3 (pSTAT3) and compared with STAT3 mutation and clinical subtypes of ATLL. We found that the expression of pSTAT3 is detected in ATLL cells except for the lymphoma type, and that the prevalence of cells positive for pSTAT3 correlates with favorable overall and progression‐free survival exclusively in the smoldering type. In contrast, mutation of STAT3 was not significantly correlated with clinicopathological findings in ATLL.

CD28, one of the costimulatory molecules, has a pivotal role in T‐cell activation, and its expression is strictly regulated in normal T cells. Gain‐of‐function genetic alterations involving CD28 have been frequently observed in adult T‐cell leukemia/lymphoma (ATLL). These abnormalities, such as CD28 fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80/CD86) was infrequently overexpressed in 12 (11%). Compared with non‐overexpressers, CD28 overexpressers showed a higher frequency of CD28 genetic alterations and had an increased number of CD80/CD86‐positive non‐neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non‐overexpressers (P = .001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance. The aim of the present study was to determine the clinicopathological significance of CD28 overexpression in adult T‐cell leukemia/lymphoma (ATLL). CD28 overexpression is associated with unfavorable prognosis of ATLL patients who were treated with multidrug regimens including mogamulizumab; thus, CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL.

Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.