Lymphomas represent a significant cause of morbidity and mortality in the United States with over 40,000 new cases in 1994 and an incidence of approximately 16/100,000 population. These statistics are further compounded by the 4% annualized rise in the incidence of lymphomas with an overall 150% increase between the 1940?s and 1980?s. Furthermore, among most lymphoma cell types, mortality has remained largely unchanged at approximately 19,000 deaths per year. My research interest is in the clinical development of novel therapeutic strategies for lymphomas and chronic leukemias (CLL). These studies complement the overall mission of the Department of Experimental Transplantation and Immunology (DETI) in several ways. A focus of the Department is the development of novel treatments for hematologic diseases with one emphasis on immunological approaches through immunoablative allogeneic transplantation and vaccine driven autologous cell mediated anti-tumor reactivity. My research has focused on the development of novel drug, cytokine and antibody-based treatment of lymphomas and includes immune-based treatments with idiotype vaccines and evaluation of agents for T-cell immunoablation during allogeneic transplantation. A major focus of my clinical efforts is the development of novel treatment platforms for aggressive lymphomas, the single most common subgroup within this disease category. They are of major clinical interest because they are potentially curable, but at a low rate with available treatments, and represent a significant public health risk. Indeed, it is debatable if the incidence of cure has significantly improved over the past 25 years. I have approached these diseases from the perspective of drug resistance and developed the EPOCH-based platform based on strategies to overcome resistance. However, there are necessary constraints placed upon the development of new treatments for diseases in which there exists curable options; by their very nature, they require incremental changes to validated regimens and stepwise development. I have taken such an approach in the development of the EPOCH platform, first by constructing the regimen around in vitro studies as well as validated clinical concepts, and second through the conduct of sequential clinical trials beginning with relapsed/refractory patients. My initial study showed EPOCH to be highly active and well tolerated in relapsed/refractory patients, and led to its further modification and testing in previously untreated aggressive lymphomas. Results from this latter trial showed dose-adjusted EPOCH to be highly effective, and potentially superior to CHOP, and has led to a CALGB study to validate the results in a cooperative group setting. These studies have also led to the further development of the EPOCH platform in combination with monoclonal antibodies and kinase inhibitors (LOI), as resistance modulators, and as a platform to achieve cytoreduction in an idiotype vaccine trial, and to deplete T-cells while controlling disease in our immunoablative transplant trials. Recent results suggest that addition of rituximab may reverse bcl-2 associated drug resistance and may provide a mechanistic explanation for the putative benefit of rituximab with chemotherapy in large B-cell lymphomas. I have also extended the development of the EPOCH platform into disease entities in which we have longstanding and successful collaborative relationships, and include the treatment of HIV-associated lymphomas with the HIV and AIDS Malignancy Branch (HAMB) and the treatment of lymphomatoid granulomatosis (LYG) with the Laboratory of Pathology; both studies have produced encouraging results. Of note, these latter diseases occur in immunocompromised patients and provide models for the treatment of disease in immune depleted states. In concert with clinical endpoints are multiple experimental endpoints to help elucidate mechanisms of resistance and drug action, pharmacokinetics and pharmacodynamics, as well as to further understand the pathobiology of the diseases under study through cDNA microarray profiling, oncogene expression, measures of minimal residual disease (MRD), and immune function and response. My second clinical research focus is in the development of novel agents for lymphomas, chronic leukemias and T-cell immunoablation. In general, these are phase I and II studies of agents with novel mechanisms of action, which are open to patients with relapsed or refractory lymphomas. Presently, my interest is in agents which may act as chemo-sensitizers by modulating apoptosis, such as monoclonal antibodies and protein kinase inhibitors. Furthermore, I am interested in identifying and testing agents with activity against T-cells, in an effort to develop new approaches to T-cell depletion for immunoablative transplants. Important components of these efforts include the study of drug pharmacology and action, effects on T-cell function and viability, the biology of lymphomas and leukemias, and the use of high technology instruments such as cDNA microarray profiling. We have recently submitted a LOI to perform a study of the proteosome inhibitor, PS-341 in relapsed and refractory large B-cell lymphomas. Work from Dr. Staudt's laboratory shows overexpression of NF-Kappa-B in the activated B-cell like subtype of large B-cell lymphomas which portends are worse prognosis. Hence, inhibition of this pathway by PS-341 may increase the efficacy of chemotherapy. The endpoints of this study will be to assess PS-341 as a single agent, to assess its toxicity with chemotherapy and to perform molecular endpoints of evaluation of NF-Kappa-B pathways in patient samples and to correlate this with response. Accomplishments: ? Completed development and evaluation of EPOCH chemotherapy in relapsed lymphoma ? Showed relationship between p53 mutation, tumor proliferation rate and bcl-2 expression, and drug resistance in lymphoma ? Completed evaluation of dose-adjusted EPOCH in untreated large B cell lymphomas and showed 74% progression-free survival at a median follow-up of 40 months. ? Completed evaluation of dose-adjusted EPOCH in untreated HIV-associated lymphomas and showed 81% progression-free survival and 100% disease-free survival at a median follow-up of 33 months. ? Showed effect of chemotherapy on CD4 dynamics and viral load in HIV-associated lymphomas, and assessed the safety of withholding antiretroviral treatment during chemotherapy for HIV-associated lymphomas ? Demonstrated the etiology of lymphomatoid granulomatosis (LYG) to be an EBV-B cell lymphoproliferative disorder. ? Assessed immunodeficiency associated with LYG and showed efficacy of interferon. ? Assessed activity and toxicity of escalated 9-aminocamptothecin in relapsed lymphomas. ? Obtained preliminary data on cDNA microarray profiling of CLL and effects of fludarabine. ? Provided preliminary data showing reversal of bcl-2 associated resistance by rituximab in large B-cell lymphomas. ? Participated in study showing new molecular subtypes of large B-cell lymphomas by cDNA-microarray profiling. ? Began a trial of EPOCH and rituximab in large B-cell lymphomas ? Showed effect of dynamic dosing on pharmacokinetics of chemotherapy for large-B cell lymphomas.
