Medicine (RMH) - Theses
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ItemImproving the outcome of patients with lymphoproliferative disorders( 2014)Lymphoproliferative disorders (LPD) collectively form the commonest category of haematologic malignancy in Australia. Most patients are not cured and improvements in treatments are urgently needed. Within this thesis I have taken two broad approaches to this problem. Optimising standard therapies 1. Using PET-CT in identify patients at risk of early disease relapse The identification of patients at highest risk of failing existing therapies is a rational starting point to improve outcomes. Using clinical datasets from Peter MacCallum Cancer Centre, I studied the ability of PET-CT to identify patients at risk of disease relapse. Theoretically, early detection of relapse when tumour burden may increase the probability of successful salvage therapy and ultimate cure. Therefore I reviewed the outcomes and method of detecting relapse patterns in patients with de novo DLBCL and transformed indolent lymphoma. No clear benefit from a surveillance strategy was demonstrated, meaning that patients can be spared the anxiety and radiation of scanning. I also explored the role of PET-CT in primary mediastinal B-cell lymphoma and found negative end of treatment PET-CT was predictive of excellent progression-free survival, but positive scans require histologic confirmation prior to escalation of therapy. 2. Central nervous system (CNS) relapse in aggressive NHL This complication is typically rapidly fatal and identifying patients at increased risk In the first study I analysed a group of high-risk patients with DLBCL and found that the addition of high dose systemic methotrexate and/or cytarabine was associated with lower rates of CNS relapse compared with intrathecal prophylaxis alone. This finding highlights the benefits obtaining when a customised therapeutic approach is used. In a second study, by collaborating through a large, international multicentre network I collated a large series of patients with mantle cell lymphoma who developed CNS relapse. Within this, I identified blastoid histology, high mantle cell lymphoma international prognostic index, raised serum lactate dehydrogenase and poor performance status as risk factors for CNS involvement. Developing new therapies The second half of this thesis focuses on the development of novel therapeutic strategies. 3. NMP and anti-CD20 monoclonal antibodies in lymphoma N-methyl-2-pyrrolidone (NMP) shares biologic properties with the established anti-cancer immune modulating drug lenalidomide, which is active with rituximab in lymphoma. I have shown that NMP has in vitro enhancement of rituximab-mediated induction of antibody dependent cellular cytotoxicity on lymphoma cell lines. The promising pre-clinical activity of this combination will be assessed in future clinical trials. 4. Rational clinical trial design using immunotherapies Finally, I designed three early phase clinical trial protocols using immunotherapies: 1) oral NMP in myeloma, 2) intra-tumoral αgalactoceramide and CpG and 3) ISCOMAB and rituximab, in indolent B-cell lymphoma. These clinical trial protocols combine correlative scientific with clinical endpoints and are now ready for activation.