The Emerging Role of Ibrutinib in the Treatment of Chronic Lymphocytic Leukemia

Stefano Molica

Disclosures

Expert Rev Hematol. 2013;6(5):543-546. 

In This Article

Abstract and Introduction

Abstract

Drugs that selectively inhibit Bruton's tyrosine kinase (BTK), such as the new orally administered agent ibrutinib, are currently under investigation for the treatment of several types of B-cell malignancies. In this article, the authors present results of a Phase Ib/II study of ibrutinib in 85 patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The enthusiasm generated by this paper relies on the fact that ibrutinib given orally on a daily basis produces very high response rates that are durable with minimal side effects. Interestingly, the favorable therapeutic index of ibrutinib may facilitate its use in combination with other agents active in the treatment of CLL. In addition, the use of an effective oral agent like ibrutinib whose efficacy does not translate into a high burden of toxicity should be considered in choosing therapy in the elderly. A challenging issue with ibrutinib is the possibility of overcoming chemotherapy in the treatment of CLL.

Introduction

A major progress in chronic lymphocytic leukemia (CLL) treatment has been represented by the introduction of chemoimmunotherapy. Accordingly, fludarabine, cyclophosphamide and rituximab (FCR), a combination tested in the recent CLL8 trial represents the gold standard of therapy for younger and fit CLL patients.[1] However, FCR cannot abrogate the poor response to chemoimmunotherapy related to the presence of 17p deletion, furthermore an extensive use of FCR is compromised by comorbidities and poor performance usually present in elderly, the most prevalent CLL population.[1–3] In this scenario, the paper recently published by Byrd et al. dealing with the use of ibrutinib in relapsed or refractory CLL or small lymphocytic lymphoma (SLL) represents an important step forward in the treatment of CLL.[4]

Ibrutinib (Pharmacyclics, Inc., Sunnyvale, CA, USA) is an orally bioavailable, potent inhibitor that covalently binds to the cysteine-481 amino acid of the Bruton's tyrosine kinase (BTK) enzyme CLL.[5] BTK, an essential component of B-cell-receptor (BCR) signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.[6] Consequently, targeting this kinase is an attractive strategy and a recently published Phase I study of ibrutinib showed significant clinical antitumor activity in patients with relapsed or refractory B-cell cancers.[7–9] These encouraging results led to start this Phase Ib/II study including CLL patients with relapsed or refractory disease who received two different doses of inbrutinib.[4]

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