Definition, Prognostic Factors, Treatment, and Response Criteria of Adult T-Cell Leukemia-Lymphoma: A Proposal From an International Consensus Meeting

Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-lymphocytic malignancy associated with a retrovirus designated human T-cell lymphotropic virus type I (HTLV-1). The diversity in clinical features and prognosis of patients with this disease has led to its subclassification into the following four categories: acute, lymphoma, chronic, and smoldering types. The chronic and smoldering subtypes are considered indolent and are usually managed with watchful waiting until disease progression, analogous to the management of some patients with chronic lymphoid leukemia (CLL) or other indolent histology lymphomas. Patients with aggressive ATL generally have a poor prognosis because of multidrug resistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications as a result of a profound T-cell immunodeficiency. Under the sponsorship of the 13th International Conference on Human Retrovirology: HTLV, a group of ATL researchers joined to form a consensus statement based on established data to define prognostic factors, clinical subclassifications, and treatment strategies. A set of response criteria specific for ATL reflecting a combination of those for lymphoma and CLL was proposed. Clinical subclassification is useful but is limited because of the diverse prognosis among each subtype. Molecular abnormalities within the host genome, such as tumor suppressor genes, may account for these diversities. A treatment strategy based on the clinical subclassification and prognostic factors is suggested, including watchful waiting approach, chemotherapy, antiviral therapy, allogeneic hematopoietic stem-cell transplantation (alloHSCT), and targeted therapies.

Download Full-text

Deregulation of microRNA involved in hematopoiesis and the immune response in HTLV-I adult T-cell leukemia

Blood ◽

10.1182/blood-2008-11-189845 ◽

2009 ◽

Vol 113 (20) ◽

pp. 4914-4917 ◽

Cited By ~ 102

Author(s):

Marcia Bellon ◽

Yves Lepelletier ◽

Olivier Hermine ◽

Christophe Nicot

Keyword(s):

T Cell ◽

Cell Lines ◽

Ex Vivo ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Hematopoietic Stem ◽

Adult T Cell Leukemia ◽

Infected Cells

Human T-cell leukemia virus type-I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease. MicroRNAs (miRNAs) are differentially expressed during hematopoiesis and lineage commitment of hematopoietic stem cell progenitors (HSCPs). Here, we report aberrant expression of hematopoietic-specific miR-223, miR-181a, miR-150, miR-142.3p, and miR-155 in HTLV-I–infected cells in vitro and uncultured ex vivo ATL cells. Our results suggest that HTLV-I–infected cells have an unbalanced expression of miRNA that favors T-cell differentiation. We also found altered expression of miRNA previously recognized as innate immunity regulators: miR-155, miR-125a, miR-132, and miR-146. Strikingly, our data also revealed significant differences between ex vivo ATL tumor cells and in vitro HTLV-I cell lines. Specifically, miR-150 and miR-223 were up-regulated in ATL patients but consistently down-regulated in HTLV-I cell lines, suggesting that ATL cells and in vitro–established cells are derived from distinct cellular populations.

Download Full-text

Clinical Characteristics and Outcomes of 102 Patients with Adult T-Cell Leukemia/Lymphoma in Peru.

Blood ◽

10.1182/blood.v114.22.5001.5001 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5001-5001

Author(s):

Brady Beltran ◽

Domingo Morales ◽

Pilar Quinones ◽

Jorge Castillo

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Prognostic Factors ◽

T Cell ◽

Performance Status ◽

Bone Marrow Involvement ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

Abstract Abstract 5001 Background Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease associated with the human T-lymphotropic virus type-I (HTLV-I). ATLL has heterogeneous clinical presentations and outcomes. Shimoyama's ATLL classification includes acute, lymphomatous, chronic and smoldering subtypes. The objective of this study is to define prognostic factors for survival in patients with ATLL. Methods 102 ATLL cases were collected in our center between January 1997 and September 2008. A diagnosis of ATLL was made according to the following criteria: a clinical history consistent with ATLL, a positive HTLV-1 antibody by ELISA and Western Blot or evidence of HTLV-1 proviral integration by PCR, and histological findings compatible with ATLL. Descriptive statistics were used to assess categorical and continuous variables. Survival curves for OS were estimated using the Kaplan-Meier method and compared using the log-rank test. For the multivariate analysis, the Cox Proportional-hazard regression test was used. Results The median age at diagnosis was 60.5 years (range 23–92 years), with a female-to-male ratio of 1.2:1. Forty nine cases (48%) had a performance status ≥ 2. Clinical types were acute (n=45), lymphomatous (n=43), smoldering (n=3), cutaneous (n=10) and chronic (n=1). Median hemoglobin was 12.0 g/dl (range 5.2–17.4 g/dl), median albumin was 3.3 g/dl (range 1.8–4.6 g/dl), median beta-2 microglobulin was 4.4 g/dl (range 1.1–16.9 g/dl), and LDH was 808 UI/ml (range 298–13000 IU/ml). Twenty nine patients with acute ATLL were treated with chemotherapy obtaining an overall response rate (ORR) of 14% (4/29), 3 complete responses (CR) and 1 partial response (PR), while in 38 patients with lymphomatous ATLL, an ORR of 32% (12/38) was obtained, 8 CR and 4 PR. Smoldering and cutaneous ATL types received mainly topic treatments. Median overall survival (OS) was 2.4 months for the acute type, 11.4 months for the lymphomatous type, 17.2 months for the smoldering type and 39.4 months for the cutaneous type (p<0.00001 for trend). In the univariate analysis, presence of B symptoms (median OS 5.4 vs. 20.2 months; p=0.005), performance status ≥ 2 (median OS 3.5 vs. 15.6 months; p<0.005), clinical stage > 2 (median OS 5.7 vs. 39.4 months; p<0.005), high LDH levels (median OS 4.3 vs. 15.4 months; p<0.005), and bone marrow involvement (median OS 3.3 vs. 15.6 months; p<0.005) were associated with worse prognosis. In the multivariate analysis, bone marrow involvement and elevated LDH remained as adverse prognostic factors for survival. Conclusions ATLL is a heterogeneous disease with poor outcomes. Each ATLL subtype has distinct clinical features, including response rates and survival times. In this cohort of 102 cases, bone marrow involvement and elevated LDH levels were independent prognostic factors. Prospective studies are needed to further validate these observations. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Mogamulizumab Therapy for Adult T-Cell Leukemia-Lymphoma: A Retrospective Multicenter Study

Blood ◽

10.1182/blood.v126.23.2703.2703 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2703-2703

Author(s):

Masahito Tokunaga ◽

Kentaro Yonekura ◽

Daisuke Nakamura ◽

Kouichi Haraguchi ◽

Tomohisa Tabuchi ◽

...

Keyword(s):

T Cell ◽

Conflicts Of Interest ◽

Objective Response ◽

Disease Status ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Hematopoietic Stem ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia

Abstract Introduction: Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell malignancy, which is caused by human T-cell leukemia virus type I (HTLV-1) and is considered to be derived from regulatory T cells (Treg). ATL is usually resistant to conventional chemotherapies and the patients with ATL have very poor prognosis. Mogamulizumab (Moga) is a humanized monoclonal antibody against CC chemokine receptor 4 (CCR4) which is expressed on T-helper type 2, Treg and tumor cells from most patients with ATL. It was reported that Moga used to treat ATL with 50% efficacy in a phase II study and frequently developed cutaneous adverse reactions (CAR). In that study, development of CAR was reported to be closely associated with the response to Moga therapy. To confirm efficacy and safety of Moga therapy for ATL, we retrospectively analyzed relapsed or refractory ATL patients who were treated by Moga at 4 institutes in Kagoshima, one of the endemic areas of HTLV-1 infection, Southwestern Japan. Patients and methods: There were 77 patients, who were received Moga therapy between March, 2007 (phase I study) and December, 2014. We studied about backgrounds (age, sex, subtypes of ATL, ECOG performance status (PS) at diagnosis and clinical stage) of the patients, contents of prior therapy and the response, prognostic index for acute and lymphoma type ATL (ATL-PI), PS and disease status at Moga therapy, response and adverse events (AE) of Moga therapy, and the survival. Results: Enrolled patients were 44 men and 33 women, and median age at Moga therapy was 65.6 years (range: 44-83 years). They consisted 54 acute, 18 lymphoma, and 5 chronic type ATL, and ATL-PI was low in 18, intermediate in 43 and high in 16 patients. Initial induction chemotherapies were mainly VCAP-AMP-VECP regimen in 41, CHOP like regimen in 19 patients. Median duration between diagnosis and Moga therapy was 8.1 months (range: 0.5-94.9 months). They were administered Moga median 5 cycles (range: 1-10 cycles). Disease status at Moga therapy were 23 relapsed and 54 refractory [partial response (PR): 8, stable disease (SD): 15, progressive disease (PD): 31] disease. Myelosuppression associated with Moga, development of cytomegalovirus antigenemia (19.5%) and other AE were tolerable. Best objective response rate was 42.9% including 18 complete remission (CR) and 15 PR. Fifty-four patients died after Moga therapy (50 from ATL, 4 from infection and so on). Median overall survival (OS) time from Moga therapy was 7.7 months (95%CI: 5.1-11.2 months) and 3-year OS rate was 18.2%. The cohort included 27 patients over 70 years, but their survival was no worse than younger. Twelve patients received allogeneic hematopoietic stem cell transplantation after Moga therapy, but had no survival advantage. Twenty-four patients suffered from CAR, which were developed median 7 cycles (range: 2-8 cycles). The severity of CAR according to CTCAE v3.0 was grade 1 in three, 2 in eight, 3 in eleven and 4 in two patients, respectively. In patients (n = 51) received Moga more than 4 cycles, 22 patients suffered from CAR and their OS (3-year OS: 43.6%) was significantly better than patients without CAR (median OS: 23.4 vs 7.9 months, p = 0.0003). Discussion: Moga therapy is effective and safe for ATL patients and the onset of moderate CAR is a favorable sign of the efficacy. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Analysis of prognostic factors in patients with adult T-cell leukemia/lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8575 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8575-8575

Author(s):

B. E. Beltran ◽

D. Morales ◽

P. Quiñones ◽

R. Salas ◽

J. Castillo

Keyword(s):

Prognostic Factors ◽

T Cell ◽

Risk Stratification ◽

Latin American ◽

Risk Group ◽

Univariate Analysis ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

8575 Background: Adult T-cell leukemia/lymphoma (ATLL) is associated with human T-cell lymphotropic virus type-I (HTLV-1) described in Southern Japan, Europe, Caribbean and South America. Risk-stratification tools for ATLL have not been adequately evaluated. This study attempts to define prognostic factors for patients with ATLL. Methods: A total of 102 cases from our Institution were collected between January 1997 and September 2008. Diagnosis was based on clinical history and histological findings consistent with ATLL and either positive HTLV-1 serology or evidence of HTLV-1 integration. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were evaluated using log-rank and Cox regression tests, respectively. Results: Median age was 61 years with a female:male ratio of 1.15:1. Clinical types were acute (n=45), lymphomatous (n=43), cutaneous (n=10), smoldering (n=3) and chronic (n=1). Median OS for acute, lymphomatous, smoldering and cutaneous subtype were 2, 11, 17 and 39 months, respectively (log-rank 28.5, p<0.00001). In the univariate analysis, presence of B symptoms, ECOG performance status 2, clinical stage II or higher, elevated LDH level and bone marrow (BM) involvement were independent factors for survival with p<0.05. The IPI score was available in 92 patients; 13 (14%), 12 (13%), 29 (32%) and 38 (41%) patients were low, low-intermediate, high-intermediate and high-risk, respectively. Median OS by IPI risk group was 40, 13, 6 and 2 months, respectively (p<0.005). The prognostic index for T-cell lymphoma (PIT) score was determined in 80 patients; 20 (25%), 17 (21%), 33 (41%) and 10 (13%) patients had scores of 0–1, 2, 3 and 4, respectively. Median OS by PIT risk group was 19, 5, 3 and 2 months, respectively (p<0.005). In multivariate analysis, BM involvement and elevated LDH were significant for survival. Conclusions: This retrospective series represents the largest Latin-American experience on ATLL, which is a heterogeneous disease with distinct clinical features and outcomes. The IPI ant PIT scores, used for risk-stratification of aggressive B-cell and peripheral T-cell lymphomas, respectively, appear as good prognostic indicators for ATLL as well. Further research is needed to better risk-stratify this unique lymphoma. No significant financial relationships to disclose.

Download Full-text

Evidence for the interleukin-2 dependent expansion of leukemic cells in adult T cell leukemia

Blood ◽

10.1182/blood.v70.5.1407.1407 ◽

1987 ◽

Vol 70 (5) ◽

pp. 1407-1411 ◽

Cited By ~ 45

Author(s):

M Maeda ◽

N Arima ◽

Y Daitoku ◽

M Kashihara ◽

H Okamoto ◽

...

Keyword(s):

T Cell ◽

Receptor Gene ◽

Interleukin 2 ◽

Leukemic Cells ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

In Vitro Proliferation ◽

Adult T Cell Leukemia

Abstract Interleukin 2 (IL-2) receptor/Tac antigen is abnormally expressed on cells of patients with adult T cell leukemia (ATL) caused by infection with human T lymphotropic virus type I (HTLV-I). Twenty-five patients with ATL were examined to determine whether their leukemic cells continued to show IL-2-dependent proliferation. In 21 patients, the in vitro proliferation of HTLV-I-infected nonleukemic T cell clones was found to be dependent on IL-2. However, clonality analysis based on T cell receptor gene rearrangement profiles and the site of HTLV-I provirus integration revealed IL-2-dependent growth in leukemic cells in four patients with ATL. These results provide evidence for the IL-2- dependent proliferation of leukemic cells in some ATL patients.

Download Full-text

Human T-cell lymphotropic virus type I (HTLV-I) antibodies in pre-diagnostic serum of patients with familial adult T-cell leukemia/lymphoma (ATL)

Hematological Oncology ◽

10.1002/hon.2900080308 ◽

2006 ◽

Vol 8 (3) ◽

pp. 169-176 ◽

Cited By ~ 1

Author(s):

Abraham M. Y. Nomura ◽

Eugene T. Yanagihara ◽

William A. Blattner ◽

Gloria Y. F. Ho ◽

Melvin S. Inamasu ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Human T Cell

Download Full-text

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

International Journal of Cancer ◽

10.1002/ijc.21688 ◽

2006 ◽

Vol 118 (12) ◽

pp. 3054-3061 ◽

Cited By ~ 50

Author(s):

Atsushi Inagaki ◽

Takashi Ishida ◽

Toshihiko Ishii ◽

Hirokazu Komatsu ◽

Shinsuke Iida ◽

...

Keyword(s):

T Cells ◽

Prognostic Factors ◽

T Cell ◽

Regulatory T Cells ◽

Clinical Significance ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Interleukin 5 ◽

Adult T Cell Leukemia

Download Full-text

Adult T-cell leukemia/lymphoma: report of two cases

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86822008000300012 ◽

2008 ◽

Vol 41 (3) ◽

pp. 288-292 ◽

Cited By ~ 4

Author(s):

Ricardo Aparecido Olivo ◽

Fabrício Frederico Mendes Martins ◽

Sheila Soares ◽

Helio Moraes-Souza

Keyword(s):

T Cell ◽

Clinical Laboratory ◽

Skin Lesions ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Laboratory Findings ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

Disease Case

Adult T-cell leukemia/lymphoma is a lymphoproliferative disorder of mature T lymphocytes associated with infection with human T-cell lymphotrophic virus type I (HTLV-I). Adult T-cell leukemia/lymphoma is characterized by clinical and laboratory polymorphism that allows it to be classified into four distinct subgroups: smoldering, chronic, acute and lymphomatous types. We present here two cases of adult T-cell leukemia/lymphoma, respectively in the acute and lymphomatous forms of the disease. Case 1 was a 35-year-old woman who presented abdominal distension accompanied by hepatosplenomegaly, adenomegaly, skin lesions, positivity for anti-HTLV-I antibodies and leukocytosis with the presence of flower cells. Case 2 was a 38-year-old man who was admitted with generalized lymphadenomegaly, positivity for anti-HTLV-I antibodies, hypercalcemia and osteolytic lesions. In this paper, we correlate the clinical-laboratory findings of these two cases with data in the literature.

Download Full-text

Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

Blood ◽

10.1182/blood-2007-09-113654 ◽

2008 ◽

Vol 111 (10) ◽

pp. 5163-5172 ◽

Cited By ~ 31

Author(s):

Jing Chen ◽

Mike Petrus ◽

Bonita R. Bryant ◽

Vinh Phuc Nguyen ◽

Mindy Stamer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Ex Vivo ◽

Proximal Promoter ◽

Type I ◽

Dependent Manner ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Spontaneous Proliferation

AbstractThe etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-κB motif in its proximal promoter, whereas IL-9 receptor-α (IL-9Rα) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Rα in ATL, a neutralizing monoclonal antibody directed toward IL-9Rα inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Rα on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Rα/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.

Download Full-text