How I treat adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I. ATL carries a bad prognosis because of intrinsic chemoresistance and severe immunosuppression. In acute ATL, Japanese trials demonstrated that although combinations of chemotherapy improved response rate, they failed to achieve a significant impact on survival. Patients with chronic and smoldering ATL have a better prognosis, but long-term survival is poor when these patients are managed with a watchfulwaiting policy or with chemotherapy. Recently, a worldwide meta-analysis revealed that the combination of zidovudine and IFN-␣ is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. ATL lymphoma patients still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine/IFN. To prevent relapse, clinical trials assessing consolidative targeted therapies such as arsenic/IFN combination or novel monoclonal antibodies are needed. Finally, allogeneic BM transplantation should be considered in suitable patients. (Blood. 2011;118(7): 1736-1745) IntroductionAdult T-cell leukemia-lymphoma (ATL) is an aggressive lymphoid proliferation associated with the human lymphotropic virus type I (HTLV-I). 1,2 ATL usually occurs in people from HTLV-I-endemic regions, such as southern Japan, the Caribbean, Central and South America, intertropical Africa, Romania, and northern Iran. 3-6 HTLV-I causes transformation and clonal expansion of T cells, resulting in ATL in approximately 1%-4% of the estimated 10-20 million infected hosts, with a mean latency period of Ͼ 50 years. 3,5,7 PathogenesisThe serum of patients with ATL contains antibodies to HTLV-I, and the HTLV-I provirus is clonally integrated in most of the cases in the CD4 ϩ CD25 ϩ -activated T lymphocytes, which are the leukemic flower cells characteristic of ATL. The exact mechanism of HTLV-I-induced leukemogenesis is not fully elucidated, although HTLV-I infection appears to represent the first event of a multistep oncogenic process. 8 Oligoclonal expansions of HTLV-I-infected T cells result from expression of the viral transactivator protein Tax, which activates the viral promoter and various cellular genes, and also creates an autocrine loop involving IL-2, IL-15, and their cognate receptors. 9-12 Tax changes many cellular pathways, including activation of cAMP response element binding protein or cAMP-dependent transcription factor, adaptor-related protein complex 1, and NF-B; up-regulation of antiapoptotic proteins; repression of p53, DNA polymerase ␤, proliferating cell nuclear antigen, and the mitotic spindle-assembly checkpoint protein MAD1; and disruption of several cell-cycle regulators, including c...

Adult T-Cell Leukemia/Lymphoma

“…Patients present with constitutional symptoms, massive lymphadenopathy sparing mediastinum, cutaneous lesions, and organomegaly. 10,11 Central nervous system involvement in ATLL ranges from 0% to 25%; imaging studies are identical to those for other primary central nervous system lymphomas, characterized by multiple ring-enhancing lesions. These lesions are mostly asymptomatic and are seen more frequently in acute and lymphomatous variants, essentially during relapse or systemic ATLL.…”

“…12 Respiratory complications are more frequent in acute ATLL secondary to tumor cell infiltration or opportunistic infections, such as cytomegalovirus, Pneumocystis jiroveci pneumonia, toxoplasmosis, and bacterial abscess or sepsis. 10,13 The lymphomatous variant is an aggressive advanced disease resembling acute-onset subtype. Marked lymphadenopathy without leukemia is a prominent feature.…”

“…In spite of the present treatment options, the outcome of aggressive ATLL remains dismal. 10,11 CONCLUSION Adult T-cell leukemia/lymphoma is a malignant lymphoproliferative neoplasm of mature T cells caused by HTLV-1, with characteristic clinicopathologic features. In spite of a greater understanding of the pathogenesis of ATLL, optimal treatment is yet to be determined and overall prognosis remains dismal.…”

Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP

“…ATL carries a very poor prognosis because of intrinsic chemoresistance and severe immunosuppression. [1][2][3][4][5][6] ATL usually occurs in individuals from HTLV-I endemic regions, such as southern Japan, the Caribbean, Central and South America, inter-tropical Africa, Romania and northern Iran. HTLV-I causes transformation and clonal expansion of T cells, resulting in ATL in~1-4% of the estimated 10-20 million infected hosts, with a mean latency period of 450 years.…”

miR-28-3p Is a Cellular Restriction Factor That Inhibits Human T Cell Leukemia Virus, Type 1 (HTLV-1) Replication and Virus Infection

“…Human T-cell Leukemia virus, type 1 (HTLV-1) 2 infection is associated with a disease with poor prognosis known as adult T cell leukemia/lymphoma or HTLV-1-associated myelopathy (HAM/TSP) (1)(2)(3)(4)(5). Because the HTLV-1 virus is poorly infectious and has a very low antigenic variability, reducing the expression of viral antigens is critical in virus maintenance in vivo.…”