published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

This thesis is submitted as a PhD by Portfolio of Publications. It represents an integrated examination of the BCR-ABL oncogene as a precise indicator of treatment response, drug resistance and relapse in patients with chronic myeloid leukaemia (CML). / Thesis (PhDBiomedicalScience)--University of South Australia, 2005.

Thesis (M. Med. Sc.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 48-60)

Thesis (Ph.D.)--Victoria University (Melbourne, Vic.), 2009.

Telomeres are regions of tandem repeats at the ends of chromosomes ensuring chromosome stability or inducing replicative senescence when critically short. Telomerase extends telomeres and its catalytic subunit, telomerase reverse transcriptase is tightly regulated at multiple levels. Cancerous cells prevent telomere-mediated senescence to attain unlimited proliferation, in most cases by enhancing telomerase activity. Chronic myeloid leukaemia is characterised by the translocation, t(9;22), in haematopoietic stem cells. The resulting fusion protein exhibits constitutive tyrosine kinase activity in the cytoplasm, promoting cellular proliferation, inhibiting apoptosis and impeding cell adhesion. Changes in telomere biology have been observed in chronic myeloid leukaemic cells. The current study aimed to investigate telomere biology in 18 chronic myeloid leukaemia patients at various time intervals from date of diagnosis. Although telomeres were significantly shorter in patients compared to controls, results point to complex telomere dynamics in the malignancy. Increased telomerase activity did not necessarily accompany telomere lengthening and increased transcription of the telomerase catalytic subunit was not necessarily indicative of telomerase activity. Ultimately the current study could not detect any trends between telomere length, telomerase activity and telomerase catalytic subunit expression in chronic myeloid leukaemia patients. Together with inherent patient-to-patient variation and the high cost per assay, measurement of telomere biology does not appear to hold prognostic value in chronic myeloid leukaemia and does not warrant inclusion into a routine test repertoire.

Background: Chronic myeloid leukaemia (CML) is a haematological malignant disease involving haematopoietic stem cells. It is caused by a known reciprocal chromosomal t(9;22)(q34;q11) translocation, or known as Philadelphia chromosome. The translocation results in the formation of a chimeric BCR-ABL fusion gene. In the most recent guidelines published by NCCN and European LeukemiaNet in 2013, tyrosine kinase inhibitors (TKI) specifically inhibiting the Bcr-Abl tyrosine kinase, are the first-line therapy for patients with chronic phase CML. Imatinib is the oldest among the 3 TKI, and is the most commonly prescribed. Despite its proven therapeutic role in CML, imatinib is a drug of extreme high cost. Estimated annual drug cost is HKD$223,380for a standard 400mg adult daily dose. Therefore, this study aims to survey on the prescribing pattern of imatinib in CML patients, its funding status, response; and estimate its economic burden on the Hong Kong population. Methodology: This is a retrospective patient chart review study. All patients who were diagnosed with CML from 2003 to 2012 and were managed in QMH or QEH were reviewed. Electronic records were retrieved to see whether imatinib was started as first-line treatment within 6 months of diagnosis. The reasons for not initiating imatinib were also investigated. Patients’ response to imatinib, and funding source for the drug, were documented. Annual drug cost of imatinib was estimated from all CML patients who attended all Hospital Authority institutions in 2012 who were prescribed with the drug. Results: Total 153 patients from the 2 institutions were reviewed. One hundred twenty four (81%) of them started imatinib as first-line therapy within 6 months of diagnosis. Nine patients started second generation TKI as first-line. Among those who did not start TKI, the most common reasons are patient preference (3.9%) and financial difficulties (3.3%). Twelve paediatric patients are identified, and all but one of them started imatinib. Seventy one% patients on imatinib experienced side effects. Most frequently reported adverse reactions are thrombocytopenia, oedema and neutropenia. Twenty eight% switched to second generation TKI due to suboptimal response or intoleranceto imatinib. During their course of treatment, 46.3% patients on imatinib require social subsidy from Samaritan Fund. From the dispensing records, the average drug cost per patient per year is HK$113,902. The estimated annual cost burden on the whole Hong Kong population is HK$43,425,878. Conclusion: The prescribing rate of imatinib in chronic phase CML patients in Hong Kong is comparable to overseas prescribing rate. The drug has become a significant financial burden to patients’ family and the society as a whole. / published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Medical Sciences

Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine; and, Institute of Medical and Veterinary Science, Division of Haematology, 2005. / Title from title page of source document; viewed 19 July 2005. Bibliography: p. 157-184 of source document. Also available in print.

Understanding the factors that regulate the growth and differentiation of haemopoietic stem cells (HSC) remains a major challenge. In this study, the proliferation and differentiation of CD34+ cells from normal donors and chronic myeloid leukaemia (CML) patients was compared. The proliferation and entry of CML cells into the cell cycle was decreased relative to cells from normal donors, and greater heterogeneity in the phenotype of CML cells at the initiation of culture was observed. Analysis of phenotype concomitant with cell division also demonstrated that the differentiation of normal CD34+ cells was consistent between donors, while marked variability was observed in the differentiation of CD34+ cells from CML patients. This included expression of CD13, CD33, CD38 and HLA-DR, which were linked to cell division in normal but not CML cells. The tyrosine kinase inhibitor, imatinib, is a novel drug displaying promising results in the treatment of CML by specifically inhibiting the growth of leukaemic cells. To examine whether myelosuppression observed in patients treated with imatinib may arise from inhibition of normal haemopoiesis, imatinib was added to colony assays established using cells from normal bone marrow. Suppression of monocyte/macrophage growth, but not that of eosinophils or neutrophils, was observed at therapeutic concentrations of imatinib. Inhibition of monocytic differentiation to macrophages was also observed and was associated with decreased functional capacity such as altered antigen uptake, production of proinflammatory cytokines and stimulation of responder cells. The specific suppression of monocyte/macrophage differentiation and function was not due to blockade of tyrosine kinases known to be inhibited by imatinib and was consistent with an inhibition of the M-CSF/c-fms signalling pathway. This hypothesis was tested using a cell line that was dependent on M-CSF for growth and survival. Cell proliferation and phosphorylation of c-fms were inhibited at an IC50 of 1.9μM and 1.4μM imatinib respectively and this was not attributable to decreased c-fms expression. These important findings therefore identify c-fms as a further target of imatinib, and suggest that imatinib should be considered for treatment of diseases where c-fms is implicated. This includes breast and ovarian cancer and inflammatory conditions such as rheumatoid arthritis. Potential side effects resulting from imatinib treatment must also be considered. / Thesis (Ph.D.)--School of Medicine, 2004.

Thesis (M.S.)--Brandeis University, 2009. / Title from PDF title page (viewed on May 29, 2009). Includes bibliographical references.

Resumo: Estudo retrospectivo com a finalidade de avaliar o impacto da introdução de um regime alternativo de condicionamento para transplantes de medula óssea alogênicos com doadores aparentados, totalmente compatíveis, portadores de Leucemia Mielóide Crônica, em Fase Crônica. No período de agosto de 1996 a julho de 2008, foram incluídos 158 pacientes, analisados em dois diferentes momentos: o primeiro inclui os pacientes transplantados antes de 2004, quando 72(45%) deles, foram tratados com a combinação Busulfano e Ciclofosfamida (BUCY). Neste período inicial os dados demonstraram melhores resultados nos pacientes abaixo de 30 anos. No segundo período (após 2004) o regime de condicionamento era orientado em função da idade do receptor, condições clínicas, e pelo histórico individual de comorbidades. Com um total de 86 pacientes, transplantados até o final da análise, 44(28%) deles receberam a combinação BUCY e 42(27%) indivíduos foram alocados para o protocolo envolvendo Busulfano e Fludarabina (FLUBU). As informações do grupo transplantado antes de 2004 mostram forte influência da idade do receptor, acima ou abaixo de 30 anos, na Sobrevida Global (p=0, 005), na Sobrevida Livre de Doença (p=0, 001) e na Mortalidade não Relacionada à Recaída (p=0,01). Outra observação nessa população foi a ocorrência da Doença Enxerto contra o Hospedeiro crônica, aos cinco anos, mais freqüentemente observada entre os pacientes que receberam Células Progenitoras Periféricas (92% vs 49% quando foi utilizada a Medula Óssea como fonte, p= 0, 004). Após 2004 os dois grupos de tratamento foram muito heterogêneos em relação a sua composição etária, com idade mediana superior no grupo que recebeu FLUBU (45 (28 a 54) anos vs. 28 (16 a 51) anos ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This is a retrospective study that aims to assess the impact of the introduction of an alternative conditioning regimen in stem celltransplants with allogeneic fully matched related donors, in patients with Chronic Myeloid Leukemia in Chronic Phase. From August 1996 to July 2008 we included 158 patients, tested during two different periods: the first period includes patients transplanted before 2004, when 72 (45%) of them were treated with the combination of Busulfan and Cyclophosphamide (BUCY). These data demonstrated that the outcome was better among patients below the age of 30 years. The second period comprised all patients transplanted after 2004. In this second period the choice of the conditioning regimen was based on recipient age, clinical condition and the individual history of comorbidities . With a total of 86 patients transplanted by the end of the analysis, 44 (28%) of them received the BUCY combination and 42 (27%) patients were allocated to the protocol with Busulfan and Fludarabine (FLUBU). For the group transplanted before 2004 a strong influence of recipient age (above or below 30 years old) on Overall Survival (p = 0.005), Disease-free Survival (p = 0.001) and Mortality Related to Transplantation (p = 0.01) could be demonstrated. Graft Versus Host Disease, at five years, was most frequently observed among patients receiving Peripheral blood Progenitor Cells (92% vs 49%) when compared with the use of Bone Marrow as a stem cell source, p = 0.004). After 2004 the two treatment groups were very heterogeneous in relation to their age structure, with older patients receiving FLUBU (45 (28 to 54) years vs 28 (16 to 51), p < 0.0001). Although we analyzed two distinct age groups , the results were comparable in terms of Overall Survival at 3 years (p = 0.49) in Disease-free Survival at 3 ... (Complete abstract click electronic access below) / Orientador: Belinda Simões / Coorientador: Ana Lúcia Coradazzi / Coorientador: Celso Arrais / Banca: Lígia Niero-Melo / Banca: Júlio Cesar Voltarelli / Mestre