PROJECT 4: Resistance and relapse in Chronic Myeloid LeukemiaChronic myeloid leukemia (CML) poses a clinical dilemma in optimizing treatment strategy. Transplantationis curative in CML, but is associated with considerable morbidity and mortality. The tyrosine kinase inhibitor(TKI) imatinib has become an attractive 'first line' agent for CML. Use of imatinib in newly .diagnosed CPCML yields complete cytogenetic remissions in >75% of cases, nonetheless primary resistance occurs in-20% of chronic phase cases treated with imatinib, and relapse occurs at a rate of ~4%/year. Patients whorelapse, especially those with Abl point mutations, appear to have a more virulent clinical course thanexpected, and often progress to advanced phase. Studies from our group have shown that the molecular'profile' of CML patients who obtain Abl mutations is similar to advanced phase disease. Moreover, patientson imatinib who are transplanted while still in chronic phase but who exhibit imatinib resistance have asurprisingly poor transplant outcome. These findings underscore the need to search for better predictors ofresponse to imatinib, a better understanding of the mechanisms of response and progression in CML, andmore information about how these molecular markers of response and progression impact on transplantationoutcomes. Thus in Specific Aim 1, we will determine genetics of TKI response and resistance in CML.
In Specific Aim 2, we will study the association of global and Abl point mutations in CML. Lastly, in Specific Aim3 we will evaluate how TKI treatment affects transplant outcomes. We expect these studies will provide abetter understanding of why CML patients respond and relapse. We expect this will lead to better diagnostictests that can predict response, as well as giving insights to novel treatment approaches and pathways toovercome resistance and treat relapse. Moreover, the understanding of how imatinib influences transplantoutcomes is a central unanswered question in treating CML, and this project should shed light on thisquestion and the biology underlying it. While these studies are focused on CML, the principal ofunderstanding the biology behind the central question of 'who and when should we transplant?' should beapplicable to most hematological malignancies.Relevance to Public Health: This project addresses the issue of tailoring therapy to an individual's specificdisease. Thus, we will discover the biology of why some cases of CML respond to imatinib, and developtests to use on patients to predict what therapy will be most effective. While this project is specific to CML,the general strategy of understanding the genetics that determine disease progression and response totherapy should be translatable to many other types of cancer.
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