The rationale of the current study is to explore the use of combination chemotherapy together with antiretroviral agents in order to determine the efficacy and toxicity of this approach, while also examining markers of virus replication and expression, and tumor cell proliferation to gain understanding of the biological basis of this malignancy and to identify predictors of response.

Primary Endpoint:

- To determine the tolerability and efficacy (response rate) of dose adjusted bortezomib-EPOCH (DA B-EPOCH) chemotherapy combined with Raltegravir in patients with HTLV-1 associated leukemia/lymphoma (ATLL).

Secondary Endpoints:

• To evaluate the effects of DA B-EPOCH chemotherapy combined with Raltegravir on HTLV-1 DNA and RNA load, HTLV-1 integrase gene sequence, and HTLV-1 integration sites. To determine if relapsed or progressive disease is a result of renewed virus replication.
• To evaluate the relation of NFκB gene expression profile on response to DA B-EPOCH chemotherapy combined with Raltegravir.

Inclusion Criteria:

• Histologically or cytologically documented ATLL. Patients with previously untreated or treated ATLL are eligible.
• Tumors must be CD3 positive (>50% cells express CD3).
• Documented HTLV-1 infection: documentation may be serologic assay (ELISA, Western blot) Confirmation of HTLV-1 rather than HTLV-2 by differential Western blot (e.g. Genelabs Diagnostics HTLV Blot 2.4) or PCR is desirable but his result is not required prior to trial enrollment.
• Measurable disease must be present. These nodes or masses should be selected according to all of the following: they should be clearly measurable in at least two perpendicular dimensions; if possible they should be from disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.For patients with acute (leukemic) form of ATLL, measureable disease can be derived from CD4+ lymphocyte flow data on the peripheral blood and/or bone marrow.
• All stages are eligible.
• Adequate hematologic function within 14 days before enrollment: ANC>1000 cells/mm3, platelet count>75,000 cells/mm3 unless cytopenias are secondary to ATLL. All patients must be off hematologic growth factors for at least 24 hrs.
• Adequate hepatic function, transaminase <3 times the upper limit of normal unless due to to Gilbert's disease or hepatic involvement by tumor; total bilirubin ≤1.5 times the upper limit of normal
• Creatinine<2.0 unless due to lymphoma.
• Karnofsky Performance Status (KPS) at least 50
• Age at least 18. -Voluntary written informed consent before performance of any study- related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Female patients of child bearing potential must have a negative pregnancy test within 72 hrs of initiation of therapy. Female patients are either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) during the study. Male patients must agree to use two acceptable methods for contraception for the duration of the study. Women must avoid pregnancy and men avoid fathering children while in the study.
• HIV positive patients are eligible if they are receiving at least two other active anti-HIV therapies other than zidovudine or atazanavir.
• Patients with active hepatitis B (HBV) infection are eligible if they are receiving effective anti-HBV therapy.
• Inclusion of Women and Minorities: Both men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

• Acute active infection requiring acute therapy. Chronic therapy with potentially myelosuppressive agents is allowed provided that entry hematologic criteria are met.

• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

• Women who are pregnant or breastfeeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

• Patient has ≥Grade 2 peripheral neuropathy

• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator as not medically relevant.

• Patient has hypersensitivity to bortezomib, boron or mannitol.

• Patient has received other investigational drugs with 14 days before enrollment

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

  • 1.5x upper limit of normal (ULN) total bilirubin except if is determined to be related to Gilbert's disease or tumor biliary/liver involvement.