Prognosis Of Adult T-cell Leukemia-lymphoma Research Articles

Nationwide Hospital-Based Survey of Adult T-Cell Leukemia/Lymphoma in Japan.

Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of patients with ATL diagnosed in the 1980s. This article highlighted the classification and prognosis of ATL based on different surveys and focused on the comparison of data derived from the available surveys. The 11th nationwide hospital-based survey was conducted in patients with ATL diagnosed in 2010–2011 using the same method as that used in the 1980s survey. The median age of disease onset was 68 years, which was increased compared with previous surveys. While median survival of patients with the acute and lymphoma types had not improved much since the 1980s, the 4-year survival rate was higher. Little improvement in the prognosis was observed for the chronic and smoldering types. The 12th nationwide survey of patients with ATL diagnosed in 2012–2013 also showed an increase in age at onset. Further epidemiological research that includes more cases is needed to deepen our understanding of the actual state of treatment and prognosis of this disease.

Risk stratification of adult T-cell leukemia/lymphoma using immunophenotyping.

Adult T‐cell leukemia/lymphoma (ATL), a human T‐lymphotropic virus type 1 (HTLV‐1)‐associated disease, has a highly variable clinical course and four subtypes with therapeutic and prognostic implications. However, there are overlapping features between ATL subtypes and between ATL and nonmalignant (non‐ATL) HTLV‐1 infection complicating diagnosis and prognostication. To further refine the diagnosis and prognosis of ATL, we characterized the immunophenotype of HTLV‐1‐infected cells in ATL and non‐ATL. A retrospective study of peripheral blood samples from 10 HTLV‐1‐uninfected subjects (UI), 54 HTLV‐1‐infected patients with non‐ATL, and 22 with ATL was performed using flow cytometry. All patients with ATL had CD4+ CCR4+ CD26− immunophenotype and the frequency of CD4+ CCR4+ CD26− T cells correlated highly significantly with the proviral load in non‐ATL suggesting CD4+ CCR4+ CD26− as a marker of HTLV‐1‐infected cells. Further immunophenotyping of CD4+ CCR4+ CD26− cells revealed that 95% patients with ATL had a CD7− (≤30% CD7+ cells), whereas 95% HTLV+ non‐ATL had CD7+ (>30% CD7+ cells) immunophenotype. All patients with aggressive ATL had a CCR7+ (≥30%), whereas 92% with indolent ATL and 100% non‐ATL had a CCR7− (<30%) immunophenotype. Patients with nonprogressing indolent ATL were CD127+ but those with progressive lymphocytosis requiring systemic therapy had a CD127− (≤30%) immunophenotype. In summary, HTLV‐1‐infected cells have a CD4+ CCR4+ CD26− immunophenotype. Within this population, CD7− phenotype suggests a diagnosis of ATL, CCR7+ phenotype identifies aggressive ATL, while CCR7− CD127− phenotype identifies progressive indolent ATL.

Expression Pattern of Immunosurveillance-Related Antigen Is a Critical Prognostic Factor of Adult T-Cell Leukemia/Lymphoma

Introduction: Human T-cell lymphotropic virus (HTLV-1) carriers are often found in coastal areas of the Kyushu-Okinawa region in Japan. Of the patients infected with the virus, only 2-5% will develop adult T-cell leukemia/lymphoma (ATLL). ATLL is classified into four clinical subtypes as follows: acute, lymphoma, chronic, and smoldering. Chronic-type ATLL has a better prognosis compared with acute and lymphoma types. However, in half of patients, chronic-type ATLL progresses to leukemia/lymphoma crisis. Abnormal expressions of CD58 and beta-2 microglobulin (b2M) were recently reported to be involved in the immune escape mechanism of tumor cells in diffuse large B-cell lymphoma (Pasqualucci et. al. Cancer Cell 2014). In our previous study, acute-type ATLL had significantly higher rates of CD58 gene deletion, which was associated with leukemia/lymphoma crisis in chronic-type ATLL (Yoshida et. al. Cancer Res 2014). However, the clinicopathological significance of HLA expression in ATLL patients remains controversial. In addition, we previously reported that the expression of programmed cell death ligand 1 (PD-L1), one of the regulatory factors of tumor immune responses, influenced disease prognosis in ATLL patients. Especially PD-L1 expression in stromal cells in tumor microenvironments is associated with better prognosis of ATLL (Miyoshi et al. Blood 2016). The present study evaluated the clinical relevance of HLA, b2M, and PD-L1 expressions, with particular emphasis on predicting overall survival of ATLL patients.Methods: We report the clinicopathological profiles of 123 patients diagnosed as having ATLL at Kurume University (Kurume, Japan) according to the 2008 World Health Organization classification system. Among these patients, 45 had the acute type and 52 had the lymphoma type, with a median age of 66 years (range, 13-90 years). We examined the immunohistological expressions of HLA and b2M proteins in all the 123 patients by using tissue microarray. The expression patterns and clinicopathological features were also examined statistically. All data were analyzed by using the STATA software version 12.0 (StataCorp, College Station, Texas).Results: In the immunohistochemical study, 91 (74%) of the 123 patients were positive for HLA, including 60 who were cell membrane positive (HLAm+), 31 who demonstrated cytoplasmic localization (HLAcy+), and 32 who were negative for HLA (HLA−). In addition, 89 (72%) of the 123 patients were positive for b2M, including 54 who were cell membrane positive (b2Mm+), 35 who demonstrated cytoplasmic localization (b2Mcy+), and 34 who were b2M negative (b2M−). The HLAm+b2Mm+ group, which showed membrane staining for both HLA and b2M, accounted for 48 cases (39%) in the present study (Table 1). In terms of clinical features, no significant differences were found between the HLAm+b2Mm+ group and the other groups. Immunophenotypical evaluation revealed significantly higher rates of CD30-positive lymphoma cells (P = 0.004) and PD-L1-positive stromal cells in microenvironments (PD-L1+stromal cells ≥50/HPF: miPD-L1high) in the HLAm+b2Mm+ patients (P = 0.008) than in the patients in other groups. Disease-specific survival (DSS) curves showed that the HLAm+b2Mm+ group had significantly better prognosis than the other groups (Figure 1-a). Especially the HLAm+b2Mm+ group with miPD-L1high had an excellent prognosis, with a 5-year survival rate of 77% (Figure 1-b). The multivariate analysis demonstrated that the membrane expressions of both HLA and b2M in lymphoma cells with increased number of PD-L1-positive stromal cells were an independent factor of good prognosis in ATLL (Table2).Conclusions: The results of our study demonstrated the following three points: 1) The expression patterns of HLA and b2M in the patients with ATLL varied. 2) The HLAm+b2Mm+ group showed significantly better prognosis than the other groups. Especially the HLAm+b2Mm+ group with miPD-L1high demonstrated the most favorable prognosis. These results suggest that the host immune surveillance mechanism for lymphoma cells in the HLAm+b2Mm+ group with mPD-L1high is still functioning. 3) The membrane expressions of HLA and b2M in ATLL cells are useful as a predictive marker of good prognosis and increase in the number of PD-L1-positive stromal cells in tumor microenvironments. [Display omitted] [Display omitted] [Display omitted] DisclosuresAsano:Chugai: Honoraria; Jannsen: Honoraria. Ohshima:Chugai: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau.

Current Clinico-Epidemiological Characteristics of Adult T-Cell Leukemia-Lymphoma (ATL) Based on the 11th Nationwide Survey in Japan

Introduction: Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-cell lymphomacaused by human T-lymphotropic virus type I (HTLV-1), which is endemic in Japan. Only a small percentage of HTLV-1 carriers infected through breast-feeding develop the disease. Previous nationwide surveys during 1980s-2000s in Japan provided a comprehensive view on the clinio-epidemiological profiles of ATL, including the establishment of the subtype-classification (i.e., the Shimoyama criteria: acute, lymphoma, chronic, and smoldering type) based on the diversity of the clinical features and prognosis. Treatment strategies have been developed by the subtype-classification; watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive ATL. The aim of this 11th survey is to characterize the current clinio-epidemiological features of ATL in Japan in the light of previous surveys.Methods: In 2013-14, we conducted an anonymous, cross-sectional, hospital-based survey of patients with ATL who were newly diagnosed during 2010-2011 across Japan. First, we asked 2500 hospitals with departments of hematology and dermatology to participate in this survey, and then we sent questionnaires to 128 participating hospitals to accumulate data of ATL. Skilled five hematologists reviewed the data of each questionnaire sheet, and the agreements of ATL diagnosis including the subtypes between the central review and participating hospitals were evaluated using Kappa statistics. Most of the collected data were analyzed by descriptive statistics.Results: A total of 996 ATL patients were registered; of these, 41 were eliminated because of the insufficient information for the diagnosis of ATL. Overall diagnostic agreement on subtype of ATL was substantial, with a kappa value 0.71 (standard error, 0.021); most of the disagreement was within aggressive/indolent category, acute vs. lymphoma types or acute vs. unfavorable chronic types. Among the 955 evaluable patients (M/F ratio, 1.12), 70% were diagnosed in the southwest region of Japan (Kyusyu/Okinawa) where HTLV-1 is endemic, which was consistent with the past surveys. The mean age at diagnosis was 68.3 years (median 68.8, range 24.7-100.3), which was significantly higher than 60.3 years in 1994-1995 and 57.7 years in 1986-1987. The proportion of ATL patients aged over 65 years was 79 % in this survey (whereas, 48% in the 1990-1991 survey), which indicates that the allo-HSCT is not applicable to the majority of current ATL patients in Japan. The proportion of acute, lymphoma, chronic, and smoldering types was 48, 28, 10 and 13%, respectively. The proportion of smoldering and chronic types tended to be greater than previous surveys (7% and 10% in the 1988-1997 surveys combined). The proportion of subtype by age group in this survey showed that the older in age at diagnosis are, the higher proportion of lymphoma subtype (10% in those aged younger than 40 years, 20% in those 50-59, and 31% in those 70 years or older.Discussion: This 11th survey revealed several clinio-epidemiological features of current ATL in Japan different from those in past two decades. First, a considerably increasing proportion of elderly ATL patients were diagnosed, which may be expected from a recent distribution of nationwide HTLV-1 carriers in Japan (Satake, et al, 2011). Second, there is an increasing tendency in the proportion of indolent types of ATL. This may be partly influenced by participation of the dermatology departments for the first time, because early phase of ATL localized in skin were frequently diagnosed in the dermatology department. Third, the proportion of lymphoma subtype was increased with age, which suggests that aging-related unknown mechanisms may affect the subtype distribution. More detailed analysis and subsequent surveys are planned to further evaluate clinical features and the efficacy of modern therapies on prognosis of ATL. DisclosuresIshizawa:Kyowa Kirin: Speakers Bureau; GSK: Research Funding; Takeda: Research Funding; Celgin: Speakers Bureau; Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Speakers Bureau; Pfizer: Speakers Bureau. Ishida:Bristol-Myers Squibb: Honoraria. Ishida:Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Celgene K.K.: Other: Research Funding to my institution. Tobinai:Gilead Sciences: Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

Hodgkin Lymphoma-Like Adult T-Cell Leukemia/Lymphoma Shows An Indolent Clinical Course: Analysis Of 7 Cases

Adult T-cell leukemia/lymphoma (ATLL) is a human T-lymphotropic virus type-1 (HTLV-1)-associated T-cell malignancy. The clonality of T-cells with HTLV-I proviral DNA integration changes from undetectable to polyclonal, and then further to monoclonal upon malignant transformation. Analysis of proviral DNA integrated in cellular DNA has shown that leukemic cells are always infected with HTLV-I. These cells are also consistently monoclonal with respect to proviral integration, which indicates that they originated from a single cell infected with HTLV-I. On the basis of findings related to changes in peripheral blood, the clinical stage gradually progresses from carrier to smoldering, chronic and acute-type leukemia. In a previous series of studies, we and other groups characterized the histopathological changes in HTLV-I-associated lymph node lesions. In addition to the typical ATLL pleomorphic and anaplastic large cell types, we identified lymph nodes with an unusual Hodgkin disease-like histology (Hodgkin-like ATLL) in HTLV-I-positive patients. Hodgkin-like ATLL showed prodromal clinical features, but the effect of conventional therapy was poor in patients with this type of lymph node lesion and most patients later developed typical ATLL. Recently, new drugs and therapies (stem cell transplantation) for ATLL have been developed, and the prognosis of ATLL has improved. It is now believed that Hodgkin-like ATLL has a relatively better prognosis than typical ATLL. In this study, we investigated the rare Hodgkin-like morphologic variant of ATLL and reexamined its prognosis.Seven cases were retrieved from the archives of the Department of Pathology, Department of Pathology, Kurume University (from 2006 to 2010). Portions of the tissue samples were formalin-fixed, paraffin-embedded, and stained with hematoxylin-eosin (H&E). Two hematopathologists (D.N. and K.O.) reviewed all cases and classified them morphologically on the basis of WHO classification. Paraffin sections from each sample were immunostained with monoclonal antibodies against CD3, CD4, CD8, CD15, CD20, CD30, TIA1, PAX5 and CCR4. Heat-mediated antigen retrieval was performed. All analyses were performed in a single laboratory. EB virus-encoded small RNA (EBER) was detected by in situ hybridization. Other portions of the tissue samples were frozen and used for DNA isolation and gene analysis. The monoclonal or oligoclonal integration of HTLV-1 DNA was examined by digestion with EcoRI, as described previously.In all cases, serum test results were positive for HTLV-1 and proviral HTLV-1 DNA bands were found, although the bands were weaker than those usually seen in typical ATLL. The median age of patients was 60 (range 40-69), with two males and five females. Laboratory data showed an elevation of lactic dehydrogenase (LDH) in six cases. Ann Arbor staging (I/II/III/IV) was 1/0/1/5 patients. Six patients received chemotherapy, one received chemotherapy with stem cell transplantation. Two patients died within 13 and 21 months, whereas five are still alive. The median survival was 31 months (range 13 to 58 months). The five-year overall survival is 71.4%.Histologically, the lymph nodes exhibited a relatively preserved nodal architecture with diffuse infiltration of small-sized lymphocytes. Small aggregated foci or clusters of a few giant cells with irregularly lobulated nuclei were scattered throughout the expanded paracortex. In the immunohistological analysis, the giant cells were positive for CD30, CD15, and PAX5 but negative for CD20, CD3, TIA-1 and CCR4. The proliferating small lymphocytes were mainly positive for CD3, CD4 and CCR4 but negative for CD8 in all cases. All patients were positive for EBER in the nuclei of the giant cells.The clinical outcome for patients with typical ATLL is generally poor with a median survival time of less than three years. However, patients with Hodgkin-like ATLL showed an indolent clinical course and relatively good survival with 71.4% five-year overall survival. Our findings indicate that pathologists and hematologists in HTLV-1 endemic areas should be more aware of ATLL and understand this morphologic variant. Disclosures:No relevant conflicts of interest to declare.

Lymphoma Study Group of JCOG

The Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group (JCOG) was initiated in 1978 by five institutions and now has 47 members. JCOG-LSG has focused on combined modalities, dose intensification and the incorporation of new agents for major disease entities of lymphoid malignancies. More than 30 trials including 10 randomized trials have been conducted for aggressive non-Hodgkin's lymphoma (NHL), adult T-cell leukemia-lymphoma (ATL), lymphoblastic lymphoma/acute lymphoblastic leukemia, Hodgkin's lymphoma (HL), multiple myeloma, NK/T-NHL and indolent B-NHL, and correlative epidemiological and pathological studies have been performed on human T-lymphotropic virus type-I and T/B cell phenotypes. The first trials for aggressive NHL revealed significant differences in the prognosis of ATL, non-ATL T-NHLs and B-NHLs, establishing a subclassification of ATL, and leading to the establishment of standard therapies for ATL and localized nasal natural killer/T-NHL. Recently, for B-NHLs including diffuse large B-cell lymphoma, mantle cell lymphoma, and indolent B-NHLs, regimens incorporating rituximab have been evaluated. The JCOG-LSG trials for HL led to the approval of dacarbazine for the National Health Insurance in Japan. The multicenter trials by the JCOG-LSG combining new modalities such as molecular-targeting agents will contribute to further improvements in the treatment of lymphoid malignancies.

New Strategy of Adult T-cell Leukemia Treatment Targeted for Anti-tumor Immunity and a Longevity Gene-encoded Protein

Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm with a poor prognosis, developing after long-term infection with human T-cell leukemia virus-1 (HTLV-1). Multiple factors (e.g., virus, host cells, epigenetic aberrations, and immune factors) have been implicated in the development of ATL, although the underlying mechanisms of leukemogenesis have not been fully elucidated. Despite recent progress in both chemotherapy and supportive care for hematological malignancies, the prognosis of ATL is still poor; overall survival at 3 years is only 24%. New strategies for the therapy and prophylaxis of ATL (e.g., vaccines and novel molecular target agents) are still required. This article reviews new strategy of ATL treatment targeted for HTLV-1-specific cytotoxic T-lymphocytes (CTLs) and SIRT1, a longevity gene-encoded protein. HTLV-1-specific CTLs play a critical role in the host immune response against HTLV-1. We have described here the decreased frequency and function of HTLV-1-specific CD8+ T cells in ATL patients and the efficient induction of the HTLV-1-specific CTLs response in human leukocyte antigen-A* 0201-transgenic mice by the HTLV-1/hepatitis B core chimeric particle and oligomannose-coated liposomes encapsulating HTLV-1 epitope without adjuvant, suggesting that the efficient antigen delivery system and CTL induction can be exploited to develop a prophylactic vaccine model against tumors and infectious diseases. Furthermore, our studies suggest that SIRT1, a longevity gene-encoded protein, is a crucial anti-apoptotic molecule in ATL cells, and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL. These studies targeted for anti-tumor immunity such as vaccine and SIRT1 may support the new prophylactic and therapeutic approach for ATL.

Multi-Step Aberrant CpG Island Hyper-Methylation Is Associated with the Progression of Adult T–Cell Leukemia/Lymphoma

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.

Clinical Significance of Serum Th1-, Th2- and Regulatory T Cells-Associated Cytokines in Adult T-Cell Leukemia/Lymphoma: High Interleukin-5 and -10 Levels Are Significant Unfavorable Prognostic Factors.

Purpose & Experimental Design: Patients with adult T-cell leukemia/lymphoma (ATLL) are in a severely immunocompromised state, leading to frequent and severe infectious complications. Therefore, it is assumed that ATLL cells either express particular cytokines or induce their expression in host immune cells, disrupting the balanced production of cytokines and causing the host's immune system to break down. We examined the levels of serum cytokines including T helper type 1- (Th1-)associated cytokines (IFN-γ, TNF-α, and IL-2), Th2-associated cytokines (IL-4, -5, and -6), and regulatory T cell-associated cytokines (IL-10 and TGF-β1) in 94 ATLL patients, 39 asymptomatic human T-cell lymphotropic virus type-1 (HTLV-1) carriers, and 50 healthy adult volunteers, in order to clarify whether elevated levels of particular cytokines are associated with the prognosis of ATLL patients.Results: On multivariate analysis, high IL-5 and IL-10 levels were independent and significant unfavorable prognostic factors among the ATLL patients. The IL-10 level significantly increased with disease progression at each step from asymptomatic HTLV-1 carrier to ATLL of the indolent variant (chronic and smoldering subtypes) to ATLL of the aggressive variant (acute and lymphoma subtypes). Furthermore, high IL-10 was significantly associated with high LDH, indicating that the IL-10 level reflects the tumor burden. The IL-5 level was not associated with disease progression nor LDH. Among ATLL patients with the aggressive variant, high IL-5, but not high IL-10, was an independent and significant unfavorable prognostic factor on multivariate analysis.Conclusions: The present study provide novel insights into the immunocompromised state of ATLL patients, and show that measurement of serum IL-5 and IL-10 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.