Ibrutinib, Obinutuzumab, Idelalisib, and Beyond: Review of Novel and Evolving Therapies for Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is a neoplasm resulting from the progressive accumulation of functionally incompetent monoclonal B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. It is the most common leukemia in Western countries and typically occurs in elderly patients. Initial treatment of CLL often includes a first-generation anti-CD20 antibody (rituximab) with chemotherapy and is the current standard of treatment for "younger" old adults (< 70 yrs of age) or older, clinically fit patients. However, because disease progression and drug resistance are inevitable, patients typically die from their disease or treatment-related complications. Improved understanding of the B-cell receptor signaling pathway, which is essential for normal B-cell growth and tumorigenesis, has led to the development of targeted therapies, with improved short-term clinical outcomes. Ibrutinib, obinutuzumab, and idelalisib, three novel agents recently approved by the U.S. Food and Administration for CLL, all have the potential to change the treatment paradigm. In this article, we describe the pathogenesis of CLL and some of its prognostic factors. Emphasis is on the pharmacology, dosing, clinical efficacy, safety, and place of therapy of ibrutinib, obinutuzumab, and idelalisib. Investigational agents that target different parts of the CLL pathogenic pathway are also described.

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

“…However other receptors including Toll-like receptors (TLRs) also appear to signal through BTK in some non-lymphoid cells 43 . In the BCR signalling pathway BTK is positioned early on along with three other non-receptor tyrosine kinases PI3-K, LYN and SYK 44 . LYN and SYK have been shown to activate BTK in B cells 45 46 .…”

Drug Discovery Testing Compounds in Patient Samples by Automated Flow Cytometry

“… 19 The critical role of external stimulation is shown by the remarkable therapeutic activity of drugs interfering with the CLL microenvironment, namely, inhibitors of signaling through the clonotypic B cell receptors. These novel drugs constitute a major paradigm shift in CLL treatment, 20 and idelalisib, tested here, is one of them. To more closely reproduce and re-create the complexity of the in vivo microenvironment in CLL, we have developed an ex vivo assay that best promotes CLL proliferation and viability with the combination of CpG + IL2 + HS5 stromal cells + 10% human serum, that approximates a lymph node environment.…”

Ibrutinib: Implications for Use in the Treatment of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia

“…An important kinase, BTK is positioned early in the BCR signaling pathway and plays a critical role in the development, proliferation, apoptosis, and other cellular processes of normal B cells. A number of B-cell malignancies overexpress BTK, causing dysregulation of usual activities and making it a potential therapeutic target (Chung & Lee, 2014;Robak & Robak, 2012).…”

“…Ibrutinib forms an irreversible covalent bond to cysteine 481, which blocks B-cell activation and signaling. This process prevents proliferation, promotes apoptosis, and stops the malignant cells' response to prosurvival stimuli in the microenvironment (Chung & Lee, 2014;Robak & Robak, 2012). Ibrutinib also inhibits several other kinases, unlike idelalisib (Zydelig), another oral BCR inhibitor, which is a selective reversible inhibitor of PI3Kẟ (Byrd, Jones, Woyach, Johnson, & Flynn, 2014b).…”