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...