Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton’s Tyrosine Kinase Inhibition

Ajoy Dias,Dharamvir Jain

doi:10.2174/1871525712666140115143914

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial myelosuppression and infection. Treatment of CLL is now moving towards targeted therapy. The success of new class of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further search for treatment agents with novel targets to inhibit. The B cell receptor activating pathway involving the Bruton’s tyrosine kinase (BTK) is crucial in B cell production and maintenance and is an attractive therapeutic target. Ibrutinib is an oral covalent inhibitor of the BTK pathway that induces apoptosis of B cells. Early phase studies with Ibrutinib either as a single agent or in combination regimens have shown promising results with an excellent safety profile in patients with high-risk, refractory or relapsed CLL and elderly treatment-naïve patients. This review summarizes the current knowledge of Ibrutinib in the treatment of CLL.

Highlights

Chronic lymphocytic leukemia (CLL) is a post germinal center neoplasm characterized by clonal proliferation and accumulation of mature appearing lymphocytes in the blood, bone marrow, lymph nodes and spleen
Conventional fludarabine based chemoimmunotherapy has been the standard of care in young and fit patients with CLL, it still carries a risk of serious myelosuppression and infections in the frail and elderly, thereby restricting its use in this group of patients
Ibrutinib has shown good response rates in high risk patients especially those with 17p13.1 deletion and unmutated IgVH, where conventional chemotherapy has met with poor response and frequent relapses

Summary

INTRODUCTION

Chronic lymphocytic leukemia (CLL) is a post germinal center neoplasm characterized by clonal proliferation and accumulation of mature appearing lymphocytes in the blood, bone marrow, lymph nodes and spleen. Loss of function of the BTK gene inhibits B lymphocytes production due to a maturation inhibition between the pro- and pre-B cell stages. This inhibition causes an inability to make all classes of immunoglobulins, leading to recurrent severe bacterial infections and increased susceptibility to viral and parasitic infections. These mutations result in virtual absence of B cells [7, 8]. Besides CLL, BCR signaling has been identified as a central pathologic mechanism in diffuse large B cell lymphoma, mantle cell lymphoma and follicular lymphoma [9, 10]

B CELL SIGNALING

Findings

CONCLUSION