Study of Pomalidomide Combined With Modified DA-EPOCH and Rituximab in KSHV-Associated Lymphomas

Background: * Kaposi sarcoma herpesvirus (KSHV)-associated primary effusion lymphoma (PEL) and large cell lymphoma arising from KSHV-MCD are aggressive B cell neoplasms with clinicopathologic and molecular profiles distinct from other AIDS-related lymphomas. * There are no prospective studies on these rare lymphomas. Clinical experience is limited; however, reported prognosis is poor, with median survival estimated at less than 6 months using conventional CHOP-like chemotherapy. * Novel treatment is urgently needed for KSHV-associated lymphomas, and the therapeutic approach must take into account concurrent KSHV-associated malignancies which are commonly seen in this patient population * Pomalidomide, an immune-modulatory derivative (IMiD) of thalidomide has in vitro direct antitumor effect in KSHV-lymphomas as well as immune modulatory and antiangiogenic effects that may be beneficial in treating both KSHV-NHL and in many patients, concurrent KS. * Rituximab, an anti-CD20 monoclonal antibody, has recently been shown to be an active agent in the management of KSHV-MCD. Although PEL is a CD20-negative tumor, advances in the understanding the biology of KSHV-infection of B-cells, the pathobiology of IL-6 syndromes in KSHV-MCD and KSHV-NHL, and clinical experience using rituximab in the treatment of KSHV-MCD support use of rituximab in the treatment of KSHV-NHL, especially in patients with concurrent KSHV-MCD. * Modified dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA)-EPOCH is an anthracycline-based regimen that allows for personalization of dose-intensity showing that inclusion of etoposide and infusional administration decreases tumor cell resistance. * The use of DA-EPOCH in combination with rituximab for the treatment of HIVassociated diffuse large B-cell lymphoma or Burkitt lymphoma has been shown to be safe and effective. * Given the central role of controlling HIV viremia with combination antiretroviral therapy (cART) in the management of KSHV-associated malignancies, as well as the likely contribution of uncontrolled HIV viremia to PEL pathogenesis, cART will be employed as an important part of the treatment regimen. Objectives: Phase I: -Determine the maximum tolerated dose and/or recommended phase II dose of pomalidomide in combination with DA-EPOCH-R. Phase II -Evaluate overall survival in treatment-naive patients with primary effusion lymphoma treated with pomalidomide in combination with, DA-EPOCH and rituximab (DAEPOCH- RP). Eligibility: -Adult patients greater than or equal to 18 years with pathology confirmed primary effusion lymphoma, including extracavitary variant OR large cell lymphoma arising in the setting of KSHVassociated MCD. * Lymphoma that is measurable or assessable * Previously treated patients will be allowed if they have not been treated with modified DA-EPOCH or pomalidomide for KSHV-associated lymphoma * Any HIV status * Hematologic and biochemical parameters within pre-specified limits at baseline * Willing to use effective birth control, as defined in the full protocol * Neither pregnant nor breast feeding * Excluded if other serious co-morbid condition that would prohibit administration of planned chemotherapeutic intervention is present Design: * This is a phase I/ II study of pomalidomide in combination with modified DA-EPOCH-R in patients with PEL and diffuse large cell lymphoma arising in the setting of KSHVMCD. * Phase I of the study will evaluate escalating doses of pomalidomide (3 mg, 4 mg, and 5 mg) in combination with modified DA-EPOCH-R to determine safe and tolerable phase II pomalidomide dose for combination. * Treatment in both Phase I and Phase II will have three parts. Patients will receive up to 21 days of pomalidomide monotherapy (part A), followed by 6 cycles of pomalidomide in combination with modified DA-EPOCH-R (part B), and then an optional up to 12 months of pomalidomide (part C) for patients with concurrent KS, symptomatic KSHVMCD, or KSHV inflammatory cytokine syndrome (KICS). * Patients with HIV will generally be prescribed cART. * In phase I, with 3 dose levels, 9-18 patients will be accrued (3-6 patients per level). * In the phase II portion of the study, 15 evaluable patients will be enrolled over 48-60 months and 12 months follow-up after the last patient has enrolled, a 1-tailed 0.10 alpha level test would have 80% power to determine if OS curve would demonstrate a 1-year OS consistent with 45% or better and ruling out 20% or worse.