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. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia Adrian WiestnerHematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA ABSTRACT junction genes (J) in order to form a novel, unique sequence that encodes the antigen binding domain of the BCR (Figure 1). In theory, billions of different combinations are possible, generating a vastly diverse repertoire of possible antigen binding sites. However, CLL cells display a highly restricted, non-random repertoire of different immunoglobulin heavy chain variable (IGHV) region genes, suggesting that CLL cells have distinct antigen specificities. 15,18,19 Furthermore, the presence or absence of somatic mutations in the clonal IGHV gene, a mark of antigenic selection, distinguishes two major CLL subtypes; IGHV mutated (M-CLL) and IGHV unmutated (U-CLL); the latter having more than 98% sequence homology of the clonal IGHV g...

CLL: ibrutinib and transplantation ride together

“…1 In contrast, targeted therapies such as B-cell receptor inhibitors (BCRi) (ibrutinib, idelalisib) or B-cell lymphoma 2 (BCL2) antagonists (venetoclax), albeit not curative, can be given to a wide range of patients and provide results comparable to those of alloHCT with much lower toxicity. 2 Of note, treatment results with BCRi and BCL2 antagonists are likely to improve by combining these agents among themselves and/or with monoclonal antibodies. 2,3 Those facts led investigators from the European Society for Bone Marrow Transplantation (EBMT) and the European Research Initiative on CLL to refine EBMT prior recommendations and to restrict alloHCT to selected patients previously treated with one of these agents.…”

“…2 Of note, treatment results with BCRi and BCL2 antagonists are likely to improve by combining these agents among themselves and/or with monoclonal antibodies. 2,3 Those facts led investigators from the European Society for Bone Marrow Transplantation (EBMT) and the European Research Initiative on CLL to refine EBMT prior recommendations and to restrict alloHCT to selected patients previously treated with one of these agents. 4 The question we face now is: should targeted therapies replace alloHCT entirely?…”

New Agents to Treat Chronic Lymphocytic Leukemia

“…Ibrutinib, the first-in-class irreversible BTK inhibitor, has transformed the clinical management of CLL. 2 However, the kinome of ibrutinib is broad, 3 which may result in substantial toxic effects. 2 Selective BTK inhibitors include ONO/GS-4059 and acalabrutinib.…”

“…2 However, the kinome of ibrutinib is broad, 3 which may result in substantial toxic effects. 2 Selective BTK inhibitors include ONO/GS-4059 and acalabrutinib. 4 We recently reported a phase 1 trial with ONO/GS-4059 and, in parallel with the acalabrutinib study, selective BTK inhibition was associated with a marked reduction in toxic effects.…”

A targeted treatment with off-target risks

“…These two compounds are the first examples of an emerging class of targeted-therapy agent that has revolutionized the treatment of certain tumours arising from immune cells known as B cells 3,4 , and both compounds have been approved for use in treatment by the US Food and Drug Administration (FDA). The drugs, often described as B-cell-receptor inhibitors, block the action of enzymes that transmit signals from receptor proteins on B cells (Fig.…”