B cell receptor activation and effect of kinase inhibitors in CLL

ABSTRACT

i) BACKGROUND
Chronic lymphocytic leukaemia (CLL), the most common leukaemia in the western world, is a clinically and biologically heterogeneous disease. In the last 15 years, impressive improvements have been made in the treatment of CLL and chemo-immunotherapy has emerged as an excellent treatment for fit patients. Exceptions to this are sub-groups of CLL patients with TP53 deletion, fludarabine refractory CLL, early relapse following fludarabine based therapy and unfit patients. The B cell receptor pathway has been explored as a potential treatment target for B cell malignancies. Several cytosolic kinases are constitutively phosphorylated in B cell malignancies and inhibitors of these kinases are in development or approved for the treatment of B cell malignancies and autoimmune disorders. Ibrutinib (BTK inhibitor) and Idelalisib (PI3K-δ inhibitor) are the first-in-class of these subsets of drugs. These drugs have changed the treatment landscape of CLL. IciCLLe trial was an endeavour to assess the clinical, immunophenotypic and biological responses to continuous ibrutinib monotherapy in treatment naïve (TN) and relapsed or refractory (RR) CLL patients.
ii) HYPOTHESIS
Assessment of B cell receptor (BCR) signalling with continuous ibrutinib will predict the depth of clinical and biological responses in both TN and RR cohorts.
iii) AIMS
To continuously evaluate BCR kinase activation in real-time in peripheral blood and bone marrow in vivo and ex vivo response to ibrutinib; Analysis of clinical response with BCR kinase response to ibrutinib to be evaluated in TN and RR cohorts.
iv) RESULTS
Ibrutinib monotherapy in TN and RR resulted in improved haematological, clinical and radiological responses in all assessable patients. Progression-free survival (PFS) was estimated at 90% for TN cohort and was estimated at 65% for RR cohort. TN cohort had a deeper response than RR cohort in terms of BM clearance. The phosflow data confirmed the decline in steady-state and stimulated phosphorylation of BTK, SYK, ERK1/2 and AKT with continued ibrutinib therapy and this was consistent in both cohorts. Exploratory analysis was suggestive that declining steady-state and stimulated phosphorylation with IgM/IgD of assessed intracellular kinases correlated with the improving clinical response.
v) CONCLUSIONS

IciCLLe trial confirmed that ibrutinib is an effective treatment for patients with CLL.
The clinical responses correlated with biological responses in both TN and RR CLL. The depth of biological response was reflective of improved depth of clinical response.