The long range goal of this study is to identify an improved therapy for HTLV-1 associated adult T-cell leukemia/ lymphoma, and examine the biological basis for tumorigenesis and tumor remission. Although this is a rare malignancy in the United States, it is a common hematological disorder in many parts of the world, including Central and South America, the Caribbean, Japan, and Iran, and thus, information gained from this study will benefit a large patient population. Moreover, information gained from this study could provide insights into other viral induced cancers, as well as cancers not yet identified to be caused by a specific microbial agent.
The specific aims of this study are: 1. To determine the efficacy and duration of response of EPOCH chemotherapy followed by antiretroviral therapy in patients with HTLV- 1 associated leukemia/lymphoma (ATLL). This study will test the hypothesis that the remission rate and duration of ATLL can be improved over that reported in the literature by the combination of an infusional multi-agent chemotherapy regimen and antiretroviral therapy with zodovudine, lamivudine, and interferon. 2. To evaluate the effects of EPOCH chemotherapy followed antiretroviral therapy on biological markers of HTLV-1 infection/immortalization: a) HTLV-1 viral DNA and RNA load, b) HTLV-1 RNA and protein expression, c) HTLV-1 clonality, d) effects of HTLV-1 on apoptosis and cell proliferation, and e) development of antiretroviral resistance. This study will test the hypothesis that specific biological features of HTLV-1 infection predispose to ATLL, and that effective therapy will after these features to achieve remissions. Specifically, we suggest that the number of infected CD4+ cells, and/or expression of certain viral gene products may correlate with response to therapy. Furthermore, effects of HTLV-1 on inhibiting apoptosis and promoting cell proliferation will be altered by effective therapy. We hypothesize that failure of antiretroviral therapy may correlate with the development of resistant virus. This trial is a supplemental study of the AIDS Malignancy Consortium (AMC), a group of oncologists and basic researchers located at 46 sites in the US and 4 sites in Australia supported by the NCI to identify more active treatment regimens for AIDS-associated cancers. Since ATLL is not directly related to AIDS, it cannot be supported under this cooperative group's existing grant. However, since the clinical expertise in treatment of ATLL lies with a subset of investigators in the AMC, the AMC has agreed to support the proposed ATLL study by use of its established operations center and facilities.
| Ratner, Lee (2005) Pathogenesis and treatment of human T-cell leukemia virus infection. Immunol Res 32:217-23 |
| Ratner, Lee (2005) Human T cell lymphotropic virus-associated leukemia/lymphoma. Curr Opin Oncol 17:469-73 |
| Wielgosz, Matthew M; Rauch, Daniel A; Jones, Kathryn S et al. (2005) Cholesterol dependence of HTLV-I infection. AIDS Res Hum Retroviruses 21:43-50 |
| Ratner, Lee (2004) Adult T cell leukemia lymphoma. Front Biosci 9:2852-9 |
