Soluble CD30 is a new biomarker to predict two-year overall survival of adult T cell leukemia/lymphoma patients

Abstract Introduction Adult T-cell leukemia/lymphoma (ATLL) is a rare aggressive malignancy with a poor prognosis caused by HTLV-1. Miami is proximal to the Caribbean where HTLV-I is endemic, and we encounter a relatively high number of ATLL cases. Herein, we have performed the largest single institution retrospective analysis of ATLL patients (pts) to date in the U.S. We studied ATLL patient characteristics, treatment patterns, and disease outcome. In addition, we investigated the expression of IRF-4/MUM-1 in available specimens. Previously, our group demonstrated an association between lack of IRF-4/MUM-1 and response to AZT-interferon-alpha (AZT/IFNa) therapy in a small ATLL cohort. IRF-4/MUM-1 is a putative NF-kB target gene that encodes a transcription factor. IRF-4/MUM-1 expression has been associated with interferon resistance in preclinical studies, and is a poor prognostic marker in some lymphomas. One of our objectives is evaluate and validate IRF-4/MUM-1 as a potential biomarker for treatment selection and outcome in ATLL. Methods We analyzed 125 pts diagnosed with ATLL in UM/JMH between 1987 and 2013. We evaluated MUM-1 protein expression using immunohistochemistry (IHC) on either tissue sections, or cytospins prepared from CD4+-enriched peripheral blood leukemic specimens using 30% nuclear staining as a cut-off positive value, or by western blot (WB) analysis in some cases where fresh or DMSO preserved ATLL cells were not available. Kaplan-Meier survival curves, log-rank test where used for survival analysis. Mann-Whitney's U test was used to compare non-normally distributed continuous variables. Pearson's chi-squared or Fischer's exact tests were used to compare categorical variables. Results ATLL pts were 45% male and 55% female with a median age of 51 (17-91). The great majority of pts were Afro-Caribbean (82%), followed by U.S. African American (12%) and South American (6%). A total of 109 pts have been analyzed for treatment response so far, including 51 acute, 50 lymphomatous (L), 6 chronic (5 unfavorable), and 2 smoldering types. The median overall survival (OS) for acute and L was 6 and 10 months respectively, and not reached for chronic and smoldering types (figure 1). Fifty-six pts (34 acute, 14 L, 5 unfavorable chronic, 1 chronic, and 2 smoldering) were treated with high-dose AZT/IFNa as first line therapy. The complete and overall response rates (CR and ORR) after AZT/IFNa for acute/unfavorable chronic (A/UC) vs. L types were 25% vs. 0.7%, and 54% vs. 21% respectively. Seventy-seven pts received chemotherapy at some point during their treatment. The CR rate and ORR for A/UC vs. L-type pts treated with chemotherapy-based regimens were 40 % vs. 21%, and 70% vs. 77% respectively. However, we observed a significantly longer median progression-free survival (PFS) and sustained responses in pts with A/UC ATLL who achieved a CR with AZT/IFNa (168.1 wks), as compared to chemotherapy (61.1 wks), which translated into an overall survival benefit. Next, in order to determine whether IRF-4/MUM-1 predicted response to AZT/IFNa, 66 ATLL cases were analyzed by IHC and/or WB. The results showed that 38.5% of A/UC were IRF-4/MUM-1+ as compared to 82.1% in the L type (<P.0001). Evaluable pts for AZT/IFNa response demonstrated that 55% of A/UC MUM-1(-) cases had a CR as compared to 0% in MUM-1+ pts (P=.009). In the L group, AZT/IFNa responses were minimal and were mainly limited to stable disease. Subgroup analysis showed that median OS for MUM-1(-) vs. MUM-1+ in A/UC subtype was 38.4 wks vs. 27.6 wks (P=0.275) (figure 2), respectively. In the L subtype, median OS for MUM-1(-) vs. MUM-1+ was 25.7 wks vs. 60.3 wks (P=0.02) (figure 3), respectively. Finally, the median PFS in AZT/IFNa-treated A/UC pts favored the MUM-1(-) as compared to MUM-1+ cases. Conclusion Our data demonstrate that AZT/IFNa therapy is beneficial in leukemic type (A/UC) lacking IRF-4/MUM-1 expression, while L type is generally resistant to this treatment. On the other hand, IRF-4/MUM-1 expression is associated with a favorable outcome in L subtype. We have identified IRF-4/MUM-1 expression as a predictive marker that could be used in deciding upfront therapy (i.e. AZT/IFNa vs. standard chemotherapy) in leukemic ATLL subtypes. Our study findings must be confirmed and validated in a larger ATLL cohort. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Relevance of Integrated Genetic Profiling in Adult T-Cell Leukemia/Lymphoma

Blood ◽

10.1182/blood.v126.23.2643.2643 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2643-2643 ◽

Cited By ~ 1

Author(s):

Keisuke Kataoka ◽

Yasunobu Nagata ◽

Akira Kitanaka ◽

Jun-ichirou Yasunaga ◽

Masako Iwanaga ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

T Cell ◽

Research Funding ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Genetic Profiling ◽

Adult T Cell Leukemia ◽

Disease Subtype ◽

The Impact

Abstract Adult T-cell leukemia/lymphoma (ATL) is a distinct subtype of peripheral T-cell neoplasms associated with human T-cell leukemia virus type-1 retrovirus. ATL includes a heterogeneous group of patients in terms of pathological and clinical features as well as prognosis, suggesting the presence of underlying molecular pathogenesis that could explain such heterogeneity among patients. Recently, we performed an integrated molecular analysis of a large number of ATL cases and delineated a comprehensive registry of gene mutations and other genetic/epigenetic lesions in ATL. In this study, we investigated possible correlations between these genetic/epigenetic lesions and clinical/pathological phenotypes in a large set of ATL patients, with a special focus on the impact of mutations and copy number alterations (CNAs) on clinical outcome. We analyzed a total of 361 ATL samples, including acute (n = 192), lymphoma (n = 66), chronic (n = 89), and smoldering (n = 14) subtypes, for recurrent mutations and CNAs. Each subtype had characteristic genetic/epigenetic features, suggesting a distinct molecular pathogenesis therein. Aggressive (acute and lymphoma) subtypes were characterized by a higher number of mutations and CNAs including focal amplifications/deletions, hyperploid status, and CIMP phenotype, compared with indolent (chronic and smoldering) tumors. Two mutations (TP53 and IRF4) and eight focal deletions involving 1p13 (CD58), 6p21 (HLA-B), 9p21 (CDKN2A), 10p11 (CCDC7), 13q32 (GPR183), 16q23 (WWOX), 17p13 (TP53), and 19q13 (CEBPA), were more common in aggressive ATL than in indolent ATL. In contrast, showing a similar mutational distribution to those found in large granular lymphocytic leukemia, STAT3 mutations were characteristic of the indolent diseases. Gene set enrichment analysis of RNA-seq data showed a significant enrichment of MYC pathway and genes regulating cell cycle and DNA repair in upregulated genes in aggressive ATL. Next, we assessed the impact of mutations and CNVs on prognosis among 215 ATL cases, for which survival data were available. In the entire cohort, mutation in CCR4 and IRF4, focal amplification in 9p24 (CD274) and 14q32 (BCL11B), and focal deletion in 9p21 (CDKN2A) were found to be significant predictors of poor overall survival, after adjustment for disease subtype and age. Multivariate analysis revealed that disease subtype (aggressive vs. indolent) was the most significant predictor of clinical outcome in ATL. Subsequent multivariate analysis according to disease subtype showed that within the patients with aggressive ATL, older age (≥ 70 years), CCR4 mutations, and 9p24 amplification were independently associated with an adverse outcome. Based on the number of the risk factors they owned, patients with aggressive ATL were classified into three categories showing marked difference in 3-year overall survival (OS) (P < 0.001): those with no risk factors (OS, 32%), with one risk factor (18%), and with two or more (0%). Among the patients with indolent ATL, we found IRF4 and TP53 mutations, 9p24 amplification, and deletions in 9p21 and 10p11 were independently associated with reduced survival. Interestingly, these alterations, except for 9p24 amplification, were also identified as genes more frequent in aggressive ATL. More importantly, based on these risk factors, the patients with indolent ATL can be classified into two categories showing very different prognostic profiles: patients with no risk factors (OS, 89%) and those with one or more risk factors (21%) (P < 0.001, HR = 16.8, 95% CI:5.4-52.5), suggesting that patients with indolent ATL having a genetic feature of the aggressive subtypes might genetically and biologically represent a distinct subset, which should be better managed as having an aggressive disease. Among these poor prognostic factors, 9p24 amplification and CCR4 mutation are especially interesting, because these lesions might be plausible targets of available agents, including anti-PD1/PD-L1 and anti-CCR4 antibodies. In conclusion, based on the comprehensive genetic profiling, we demonstrated that the known subtypes of ATL can be further classified into genetically and biologically distinct subsets of tumors characterized by discrete sets of genetic lesions and substantially different prognosis. Our results suggest that molecular profiling can improve the prediction of prognosis in ATL patients and better guide therapy. Disclosures Tobinai: Gilead Sciences: Research Funding. Miyazaki:Shin-bio: Honoraria; Chugai: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

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Adult T-Cell Leukemia/Lymphoma: A Clinical and Epidemiological Analysis at the Medicine School of Sao Paulo University

Blood ◽

10.1182/blood.v126.23.5091.5091 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5091-5091

Author(s):

Ana Costa Cordeiro ◽

Luis Alberto de Padua Covas Lage ◽

Renata Oliveira Costa ◽

Debora Levy ◽

Juliana Pereira

Keyword(s):

Overall Survival ◽

T Cell ◽

Sao Paulo ◽

Cell Leukaemia ◽

São Paulo ◽

T Cell Leukemia ◽

Cell Leukemia ◽

First Line ◽

Adult T Cell Leukemia ◽

Average Survival

Abstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare disease described in Japan in 1977 and associated with human T-cell leukemia virus 1 (HTLV-1) infection. It is classified into four subgroups [1]: smoldering and chronic forms which are considered indolent and acute and lymphoma subtypes that present an aggressive behavior and short overall survival (OS) despite the treatment. Here, we describe an ATLL experience at a reference cancer treatment institution in Sao Paulo, Brazil. Methods: We retrospectively analyzed 29 ATLL patients who were attended from June/2006 to June/2015 at the Medicine School of Sao Paulo University, Brazil. ATLL was classified according to Shimoyama criteria [1] and Levine score [2] was used to estimate the probability of ATLL diagnosis. All patients were HTLV-1+. In the leukemic subtypes of ATLL, the neoplastic cells were CD3+/CD4+/CD8- or CD3+/CD4-/CD8- along with CD25+ and lack of CD7 expression. In the lymphoma type all patients showed a peripheral T cell lymphoma on their tissue biopsy. Statistical analysis was performed using GraphPad Prism Version 5.0 software. Results: Table 1 shows the clinical characteristics of patients on diagnosis. Acute ATLL was associated with higher Levine's score. The average age on diagnosis was 48.82 years old (18.69-74.26). Our data is in accordance with previous Brazilian studies that showed lower average age on diagnosis. This could be related to earlier infection, intrinsic characteristics of virus strains circulating in Americas or host immune particularities. There was confection with B hepatitis, C hepatitis and HIV in three, two and one case, respectively. Forty-five per cent of the patients had skin lesions and eight patients presented central nervous system disease (4 of acute ATLL). No patient had concomitant HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis. In our practice, smoldering ATLL was usually held in a watchfull-waiting approach. All six chronic ATLL patients were treated with interferon alpha and zidovudine (IFN+AZT) first-line. Progression-free survival (PFS) was 36.06 months and 12.4 months for smoldering and chronic subtypes, respectively. Acute and lymphoma subtypes had been treated with polichemotherapy, usually with CHOEP regimen (vincristine 1,4 mg/m2 i.v D1, doxorubicin 50mg/m2 i.v D1, cyclophosphamide 750mg/m2 i.v D1, etoposide 750 mg/m2 i.v D1, dexamethasone 20 mg i.v on day 1, prednisone 100 mg days 2 to 5) first-line. Overall average survival for lymphoma ATLL was 11.57 months, shorter than previous reports (average of 16 months, 86% treated with CHOP regimen [3]; survival of 19.7 months LSG15 protocol [4]). Eleven in 15 patients with acute ATLL had died after an average of 8.5 months (2.3 - 15.5) after the diagnosis. Overall survival for all subtypes was 15.17months (fig 1A), and 59.03; 44.47; 11.75 and 5.8 months (p= 0.0634) for smoldering, chronic, lymphoma and acute subtypes, respectively (fig 1B). Conclusion: We found an OS of 5.8 months for acute ATLL treated with chemotherapy as first-line, which is comparable to literature (average survival of 6 months [3]) but shorter than those patients treated with first-line IFN+AZT (average survival of 9 months [3]). In our setting it is still scarcely available trioxide arsenic and clinical trials for ATLL, and allogenic transplant related to mortality is still high. We are therefore changing our practice according to recent recommendations and aiming to treat leukemic ATLL first-line with higher tolerated doses of IFN+AZT to improve our survival curve. References 1. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adultT-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. 1991; 79(3):428-37. 2. Levine PH, et al. AdultT-cell leukemia/lymphoma: a working point-score classification for epidemiological studies. Int J Cancer. 1994; 59(4):491-3. 3. Bazarbachi A, et al. Meta-analysis on the use of zidovudine and interferon alfa in adult t cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010; 28(27):4177-83. 4. Yamada Y, et al. A new gcsf supported combination chemotherapy LSG15, for adult T-Cell leukaemia -lymphoma: japan clinical oncology group study 9303. Br J Haematol 2001; 113(2):375-82. Table 1. Patient characteristics at diagnosis Table 1. Patient characteristics at diagnosis Figure 1. Overall survival for all casuistic (A) and for each subtype of ATLL patients (B). Figure 1. Overall survival for all casuistic (A) and for each subtype of ATLL patients (B). Disclosures No relevant conflicts of interest to declare.

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Use of Zidovudine and Interferon Alfa With Chemotherapy Improves Survival in Both Acute and Lymphoma Subtypes of Adult T-Cell Leukemia/Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2011.35.5578 ◽

2011 ◽

Vol 29 (35) ◽

pp. 4696-4701 ◽

Cited By ~ 41

Author(s):

Andrew Hodson ◽

Siobhan Crichton ◽

Silvia Montoto ◽

Naheed Mir ◽

Estella Matutes ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Interferon Alfa ◽

T Cell Leukemia ◽

Cell Leukemia ◽

First Line ◽

Adult T Cell Leukemia ◽

First Line Therapy ◽

Line Therapy ◽

The Impact

Purpose Adult T-cell leukemia/lymphoma (ATLL) is a mature (post-thymic) T-cell lymphoma associated with human T-lymphotropic virus type 1 infection. Survival in aggressive subtypes remains poor, and treatment resistance is frequent. Use of zidovudine (ZDV) and interferon alfa (IFN-α) has been associated with improved response rates in small studies and prolonged overall survival in leukemic ATLL subtypes in a recent meta-analysis. Patients and Methods We report the clinicopathologic characteristics, treatment, and outcome of 73 patients with aggressive ATLL (acute ATLL, 29; lymphoma ATLL, 44) diagnosed and treated in England between 1999 and 2009. The impact of ZDV/IFN-α on treatment response and survival was assessed. Results The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α). Median overall survival (OS) was 9 months: 7.5 months for acute ATLL and 10 months for lymphoma ATLL. Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL (hazard ratio, 0.23; 95% CI, 0.09 to 0.60; P = .002). Combined first-line therapy prolonged median OS in acute (P = .0081) and lymphoma ATLL (P = .001) compared with chemotherapy alone. Conclusion These data support the use of low-dose ZDV/IFN-α with chemotherapy in first-line treatment of acute and lymphoma ATLL.

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A Worldwide Meta-Analysis on the Use of Zidovudine and Interferon-alpha for the Treatment of Adult T–Cell Leukemia/Lymphoma.

Blood ◽

10.1182/blood.v110.11.2049.2049 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2049-2049 ◽

Cited By ~ 4

Author(s):

Ali Bazarbachi ◽

Gerard Panelatti ◽

Juan Carlos Ramos ◽

Patricia Tortevoye ◽

Zaher Otrock ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Interferon Alpha ◽

Meta Analysis ◽

Prolonged Survival ◽

T Cell Leukemia ◽

Cell Leukemia ◽

First Line ◽

Adult T Cell Leukemia ◽

Ifn Therapy

Abstract HTLV-I associated adult T cell leukemia/lymphoma (ATL) is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Multiple small phase II studies using zidovudine (ZDV) and interferon-alpha (IFN) showed response in ATL patients. However, the impact of this therapy on ATL prognosis remains to be determined. Here, we report a worldwide meta-analysis on the use of ZDV/IFN treatment for ATL in 209 patients treated from 1994 to 2006. Patients were recruited in the USA (27 patients), the UK (13 patients), Martinique (102 patients) and France metropolitaine (67 patients). Collected data included geographic origin, age, sex, type of the disease, clinical presentation, LDH levels, calcemia, and lymphocytes number. Median age was 49 years (range 16 to 95). According to Shimoyama classification, there were 98 acute ATL, 20 chronic ATL, 9 smouldering ATL, 75 ATL lymphoma, and 7 patients with an unknown subtype. Hypercalcemia was present in 60% of patients. The data concerning the course of the disease were also collected, particularly the response status, the length of the response, the duration of ZDV+IFN therapy, as well as previous and post chemotherapy treatments. One hundred patients received first line ZDV+IFN therapy. In these patients, response rate was 66%, including 43% of patients achieving complete remission (CR). Median overall survival and 5 year overall survival rate were 24 months and 50% for patients who received first line ZDV+IFN therapy, versus 7 months and 20% for patients who received first line chemotherapy. When analysis was performed by ATL subtype, patients with acute, chronic, and smouldering ATL significantly benefited from first line ZDV+IFN therapy, whereas no additional benefit was achieved in patients with ATL lymphoma. Achievement of CR with first line ZDV+IFN therapy resulted in prolonged survival of more than 10 years in 70% of the study population, and 75% of the acute ATL subgroup. Finally, first line ZDV+IFN therapy in chronic and smouldering ATL resulted in 100% overall survival at 10 years. In conclusion, these results confirm that treatment of ATL using ZDV and IFN results in a high response and CR rates particularly in acute, chronic and smouldering ATL, resulting in impressive prolonged survival and hence should be considered as gold standard first line therapy.

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Serum Soluble CD30 Levels to Detect Activation and Aggression Status of Adult T-Cell Leukemia/Lymphoma Cells

Journal of Hematology & Thromboembolic Diseases ◽

10.4172/2329-8790.1000205 ◽

2015 ◽

Vol 03 (03) ◽

Author(s):

Shigeki Takemoto

Keyword(s):

T Cell ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Lymphoma Cells ◽

Adult T Cell Leukemia ◽

Soluble Cd30

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A Lack of Cellular Senescence, Formation of Microenvironment, and Role of Soluble CD30 in Development of Adult T-Cell Leukemia/Lymphoma

Journal of Hematology & Thromboembolic Diseases ◽

10.4172/2329-8790.1000151 ◽

2014 ◽

Vol 02 (04) ◽

Author(s):

higeki Takemoto

Keyword(s):

T Cell ◽

Cellular Senescence ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Soluble Cd30

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Soluble CD30 and peripheral blood or pulmonary involvement of adult T-cell leukemia/lymphoma

Integrative Cancer Science and Therapeutics ◽

10.15761/icst.1000103 ◽

2014 ◽

Vol 1 (2) ◽

Author(s):

Shigeki Takemoto

Keyword(s):

T Cell ◽

Peripheral Blood ◽

Pulmonary Involvement ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Soluble Cd30

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Type of skin eruption is an independent prognostic indicator for adult T-cell leukemia/lymphoma

Blood ◽

10.1182/blood-2010-11-316794 ◽

2011 ◽

Vol 117 (15) ◽

pp. 3961-3967 ◽

Cited By ~ 77

Author(s):

Yu Sawada ◽

Ryosuke Hino ◽

Kayo Hama ◽

Shun Ohmori ◽

Haruna Fueki ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Survival Time ◽

Skin Eruption ◽

Median Survival ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Patch Type ◽

Adult T Cell Leukemia ◽

T Stage

Abstract Cutaneous involvement is seen in ∼ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1.

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