The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents.

Figure 1.

Generation of the BCR repertoire and chronic lymphocytic leukemia (CLL) subtypes. (A) B-cell precursors rearrange genetic sequences (V; variable; D: diversity; J: joining; C: constant) to form heavy chain (VDJ recombination) and light chain (VJ recombination) sequences that encode the antigen binding structures of the BCR. (B) Upon antigen encounter naïve B cells undergo further maturation in lymphoid tissues. BCR activation induces expression of the enzyme adenosine deaminase (AID) which introduces somatic mutations into the gene segments encoding the variable domain of the BCR. BCRs carrying amino acid substitutions that confer stronger antigen binding preferentially expand. The presence or absence of somatic mutations in the immunoglobulin heavy chain variable region (IGHV) has been used to differentiate between IGHV unmutated (U-CLL) and IGHV mutated (M-CLL) subtypes, the former apparently derived from a precursor having undergone antigenic selection, the latter carrying IGHV sequences in germline configuration as found in naïve B cells. However, the cellular derivation of CLL cells is more complex, and there is good evidence that antigen selection plays a role in both CLL subtypes.^,,

Figure 2.

BCR signaling and downstream pathways. The BCR consists of a surface transmembrane immunoglobulin (Ig) receptor associated with the Ig alpha (Igα, CD79A) and Ig beta (Igβ, CD79B) chains. BCR signaling in response to antigen binding induces LYN and SYK-dependent phosphorylation of tyrosine motifs (phosphorylation denoted by “P” in yellow circle) on CD79A and CD79B. A number of protein tyrosine kinases and the lipid kinase PI3Kδ transmit survival and proliferation signals and regulate cell maturation and migration. Small molecule inhibitors of select kinases in the BCR pathway that have demonstrated clinical activity are indicated (See text for details and references).

Figure 3.

Chronic lymphocytic leukemia (CLL) cells interact with soluble, structural, and cellular elements in the tissue microenvironment. Shown is a selection of possible interactions between CLL cells and components of the microenvironment investigated primarily in in vitro models and supportive evidence from in vivo models or observations in patients. (See text for details and references).

Figure 4.

Mechanism of BTK inhibition by ibrutinib and effect of resistance mutations. (A) Ibrutinib covalently binds to a cysteine at position 481 (Cys481) in the ATP binding pocket of BTK which leads to irreversible inhibition of the kinase molecule. Reversal of inhibition requires synthesis of new BTK molecules. (B) In patients with ibrutinib resistance, mutations that lead to replacement of Cys481 by another amino acid have been identified. In the absence of Cys481, ibrutinib cannot form a covalent bond and inhibition of the kinase is reversible and short-lived consistent with the rapid clearance of ibrutinib.