Biological Determinants of Therapeutic Response to L-Asparaginase in Children with Acute Lymphoblastic Leukaemia

UoM administered thesis: Phd

  • Authors:
  • Ashish Masurekar

Abstract

Institution: The University of Manchester Name: Dr Ashish Narayan Masurekar Degree Title: Doctor of Philosophy (PhD) Thesis title: Biological Determinants of Therapeutic Response to L-Asparaginase in Children with Acute Lymphoblastic Leukaemia.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=

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Original languageEnglish
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Award date31 Dec 2012