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Title: Biological determinants of therapeutic response to L-Asparaginase in children with acute lymphoblastic leukaemia
Author: Masurekar, Ashish
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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Introduction: Intensification of chemotherapeutic agents in use since the 1970's has led to over 80% survival in childhood ALL. The price of cure is treatment related morbidity and mortality that now approaches the incidence of relapse. Further improvement in outcome need better understanding the biological basis behind disease heterogeneity and identifying new targets and therapeutic strategies. Patients and Methods: We monitored trough ASNase activity at one or more time points in 451 patients treated in UKALL2003 and ALLR3 trials. The activity was correlated with prognostic determinants using assays mostly developed in house and data collated from the national trials. Two in-vitro models were created, one to test microenvironment mediated drug resistance and the second to test tumour related thrombosis. Results: Over 85% of patients [n=451; 427 (UKALL2003) and 24 (ALLR3)] had adequate ASNase activity levels. For UKALL2003 patients, the incidence silent neutralising antibodies (4.7%); clinical hypersensitivity (3.7%); thrombosis (3.1%) and pancreatitis (1.5%) was lower than previously reported. Hypersensitivity was mostly (n=16/17) seen in regimen C. There was a significant association between inadequate activity in induction and MRD levels in regimen A (p=0.03), especially so if they additionally had good risk cytogenetics (p=0.006). Older patients had higher incidence of inadequate ASNase activity during induction (p=0.0097). Patients in regimen C were more likely to inactivate ASNase in post induction phase (p = < 0.01); less likely to recover from inadequate response to ASNase during induction (p= < 0.01) more likely to experience toxicity to ASNase. ALLR3 patients: Silent antibodies were not observed in 16/24 patients that were tested. ASNase did not appear to influence outcome of patients in ALLR3. A model of microenvironment mediated multi-drug resistance showed a role of exosomal miRNA, of bone marrow stromal cell origin, in altering the redox state and chromatin pattern of leukaemic cell. In the second model, tumour associated microvesicles were shown to have a thrombogenic potential. Conclusion: Patients with good risk features depend on ASNase for disease clearance in the early phase. Routine testing would identify those with inadequate ASNase levels and improve the resolution of the current prognostic system used to decide post induction therapy. High risk patients have higher incidence of toxicity to ASNase and show a multidrug resistant phenotype where response to ASNase is not sufficient. A better understanding of disease biology is needed to design new treatment strategies in these patients.
Supervisor: Saha, Vaskar Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available