Second-generation Bruton's Tyrosine Kinase Inhibitor Research Articles

Dermatological Toxicities of Bruton's Tyrosine Kinase Inhibitors.

The development of Bruton's tyrosine kinase (BTK) inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other B cell malignancies. The first-generation inhibitor ibrutinib works by covalent irreversible binding to BTK, a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood)family that plays a critical role in the B-cell receptor signaling pathway. It also induces an 'off-target' inhibition of a range of other kinases including (but not limited to) epidermal growth factor receptor (EGFR), SRC, and other kinases of the TEC family (interleukin-2-inducible T-cell kinase [ITK], Tec, BMX). Dermatological toxicities are among the most common toxicities of ibrutinib, but remain of mild to moderate intensity in most cases and are readily manageable. Their incidence is highest during the first year of treatment and declines over time. In addition, it has been postulated that ibrutinib-related dermatologic adverse events are mediated by the direct binding to both BTK and other 'off-target' kinases. Bruising, ecchymoses, and petechiae represent the most characteristic dermatologic adverse events. Nail and hair changes are also common, as skin infections (opportunistic infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection), folliculitis, and other types of rashes. Panniculitis, aphthous-like ulcerations with stomatitis, neutrophilic dermatosis, peripheral edema, and skin cracking can also occur. Next-generation BTK inhibitors, acalabrutinib and zanubrutinib, have been designed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC-family kinases). These drugs have been recently FDA-approved for relapsed or refractory mantle cell lymphoma. Although the overall incidence of their toxicities is expected to be more limited, acalubrutinib and zanubrutinib are associated with a range of dermatologic toxic effects that appear to be similar to those previously described with ibrutinib, including bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. In particular, both drugs induce skin bleeding events in more than 30% of patients treated. However, the available dermatological data are still rather limited and will have to be consolidated prospectively. This review article analyses the wide spectrum of dermatological toxicities that can be encountered with first- and second-generation BTK inhibitors. Finally, recommendations for appropriate treatment as well as a synthesis algorithm for management are also proposed.

Zanubrutinib: a new BTK inhibitor for treatment of relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) has historically been an aggressive disease with poor long-term survival. In the last decade, Bruton tyrosine kinase (BTK) inhibition has emerged as a new treatment strategy for MCL, especially in the relapsed/refractory (r/r) setting. Zanubrutinib, a second-generation BTK inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in late 2019 for r/r MCL on the basis of combined overall response rate of 84% in a total of 118 patients from two multicenter clinical trials, BGB-3111-AU-003 and BGB-3111-206. Duration of response was 14-18 months. Although 57% of patients developed grade 3 and 4 adverse side effects including anemia, pneumonia and neutropenia, only 8% discontinued treatment suggesting zanubrutinib monotherapy was fairly well tolerated. As compared to first-generation ibrutinib, zanubrutinib has higher BTK selectivity which may result in fewer off-target effects and improved potential for combination with other targeted therapies. In addition to a confirmatory phase III trial, there are multiple ongoing studies evaluating zanubrutinib as part of two- and three-drug regimens in MCL and other B-cell malignancies. These current results and areas of further interest indicate an exciting future for zanubrutinib in the treatment of MCL.

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on.

A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib-resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second-generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high-risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long-term results of ongoing studies combining Ibrutinib with (chemo)-immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions.

Phase 1/2 Study of Tirabrutinib (ONO/GS-4059), a Next-Generation Bruton's Tyrosine Kinase (BTK) Inhibitor, Monotherapy in Patients with Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL)

Phase 1/2 Study of Tirabrutinib (ONO/GS-4059), a Next-Generation Bruton's Tyrosine Kinase (BTK) Inhibitor, Monotherapy in Patients with Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL)

A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Bruton Tyrosine Kinase Inhibitors: Present and Future.

Bruton tyrosine kinase (BTK) is a nonreceptor tyrosine kinase that plays a central role in the signal transduction of the B-cell antigen receptor and other cell surface receptors, both in normal and malignant B lymphocytes. B-cell antigen receptor signaling is activated in secondary lymphatic organs and drives the proliferation of malignant B cells, including chronic lymphocytic leukemia (CLL) cells. During the last 10 years, BTK inhibitors (BTKis) are increasingly replacing chemotherapy-based regimen, especially in patients with CLL and mantle cell lymphoma (MCL). Bruton tyrosine kinase inhibitors are particularly active in patients with CLL and MCL, but also received approval for Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft-versus-host disease. Current clinical practice is continuous long-term administration of BTKi, which can be complicated by adverse effects or the development of drug resistance. Alternatives to long-term use of BTKi are being developed, such as combination therapies, permitting for limited duration therapy. Second-generation BTKis are under development, which differ from ibrutinib, the first-in-class BTKi, in their specificity for BTK, and therefore may differentiate themselves from ibrutinib in terms of adverse effects or efficacy.

The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal β2-macroglobulin (β2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal β2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.

Evaluating Acalabrutinib In The Treatment Of Mantle Cell Lymphoma: Design, Development, And Place In Therapy.

Mantle cell lymphoma (MCL) is an incurable intermediate-grade lymphoma representing 5–6% of non-Hodgkin’s lymphomas diagnosed in the United States. The introduction of inhibitors of Bruton’s tyrosine kinase (BTK) into targeted therapy for MCL has significantly improved outcomes in patients with relapsed/refractory (R/R) disease. Since the initial approval of the first-generation inhibitor, ibrutinib, several second-generation inhibitors have been explored. Acalabrutinib, a second-generation BTK inhibitor, has demonstrated impressive efficacy in clinical trials along with a safety profile that thus far appears improved compared to ibrutinib. The results of a Phase II trial in patients with R/R MCL led to the approval of acalabrutinib in this patient population while fueling further exploration of acalabrutinib in several ongoing clinical trials.

The Impacts of Zanubrutinib on Immune Cells in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed cell death protein 1 (PD-1) on total CD4+, total CD8+ and T helper cells, and cytotoxic T lymphocyte-associated antigen-4 on total CD4+ (P=0.010) and regulatory T cells (P<0.05) reduced after treatment (P<0.05). There were significant differences in expression intensity of CD19 (P<0.01), C-X-C chemokine receptor type 5 (CXCR5) (P<0.01) and CD49d (P<0.05) on B cells before and after treatment. Down-regulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. The number of B cells and programmed death-ligand 1 expression down-regulated, especially in the young, CLL, normal spleen, normal I²2-macroglobulin (I²2-MG), abnormal lactate dehydrogenase (LDH) and normal tumor protein 53 subgroups, while CD49d expression tended to decrease in the male, old, CLL, splenomegaly, abnormal I²2-MG and abnormal LDH subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through down-regulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors. Funding: This study was supported by National Natural Science Foundation of China (81370657, 81470328, 81470329, 81600130, 81770166, 81720108002), Jiangsu Province’s Medical Elite Programme (ZDRCA2016022), Project of National Key Clinical Specialty, National Science & Technology Pillar Program (2014BAI09B12), Jiangsu Provincial Special Program of Medical Science (BL2014086 and BE2017751) and National Science and Technology Major Project (2018ZX09734-007). Declaration of Interest: No potential conflicts of interest were disclosed. Ethical Approval: This study was approved by the hospital ethics committee and all patients were provided informed consent according to the Helsinki Declaration of 1975.

Ibrutinib Displays Atrial-Specific Toxicity in Human Stem Cell-Derived Cardiomyocytes.

SummaryIbrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.

Differences and similarities in the effects of ibrutinib and acalabrutinib on platelet functions.

While efficient at treating B-cell malignancies, Bruton tyrosine kinase (BTK) inhibitors are consistently reported to increase the risk of bleeding. Analyzing platelet aggregation response to collagen in platelet-rich plasma allowed us to identify two groups in the healthy population characterized by low or high sensitivity to ibrutinib in vitro. Inhibition of drug efflux pumps induced a shift from ibrutinib low-sensitive platelets to high-sensitive ones. At a clinically relevant dose, acalabrutinib, a second-generation BTK inhibitor, did not affect maximal collagen-induced platelet aggregation in the ibrutinib low-sensitive group but did inhibit aggregation in a small fraction of the ibrutinib high-sensitive group. Consistently, acalabrutinib delayed aggregation, particularly in the ibrutinib high-sensitive group. In chronic lymphocytic leukemia patients, acalabrutinib inhibited maximal platelet aggregation only in the ibrutinib high-sensitive group. Acalabrutinib inhibited collagen-induced tyrosine-753 phosphorylation of phospholipase Cγ2 in both groups, but, in contrast to ibrutinib, did not affect Src-family kinases. Acalabrutinib affected thrombus growth under flow only in the ibrutinib high-sensitive group and potentiated the effect of cyclooxygenase and P2Y12 receptor blockers in both groups. Since the better profile of acalabrutinib was observed mainly in the ibrutinib low-sensitive group, replacement therapy in patients may not systematically reduce the risk of bleeding.

Acalabrutinib, A Second-Generation Bruton's Tyrosine Kinase Inhibitor.

The Bruton's tyrosine kinase (BTK) is an essential in the B-cell receptor (BCR) signaling pathway which was identified as crucial in the pathogenesis of B-cell malignancies. Ibrutinib, a first-in-class BTK inhibitor, has been approved for the treatment of distinct B-cell malignancies. To overcome off-target side effects of and emerging resistances to ibrutinib, more selective second-generation BTK inhibitors were developed. Acalabrutinib is a novel second-generation BTK inhibitor and has shown promising safety and efficacy profiles in phase 1/2 clinical trials in patients with relapsed CLL and pretreated MCL. Recently, acalabrutinib was approved by the FDA for treatment of adult patients with MCL who received at least one prior therapy. However, clinical trials on a direct comparison between ibrutinib and acalabrutinib and on combination treatment options with other agents as CD20 antibodies are warranted.

An update for Richter syndrome - new directions and developments.

High-grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy-resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics. Herein, we summarise what is known regarding the molecular drivers of RS and the existing clinical trial data, including the recently published CHOP-OR (cyclophosphamide, doxorubicin, vincristine, prednisolone and ofatumumab followed by ofatumumab maintenance in newly diagnosed RS) trial. We discuss novel agents in development with a focus on the second-generation Bruton tyrosine kinase inhibitor acalabrutinib, checkpoint inhibition and the potential role of precision medicine in future trials of RS.

A Second-Generation BTK Inhibitor for Chronic Lymphocytic Leukemia

The B-cell receptor signaling pathway is integral to the pathogenesis of most B-cell malignancies, including chronic lymphocytic leukemia (CLL). One potential target in that pathway is Bruton tyrosine kinase (BTK). Acalabrutinib (ACP-196), an irreversible BTK inhibitor, lacks much of the “off-target” binding of the first-in-class agent, ibrutinib. Investigators conducted a manufacturer-funded, uncontrolled trial of …

Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma.

Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma, yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population cells from human myeloma cell lines and multiple myeloma primary samples as surrogate for the elusive multiple myeloma stem cell, we found that elevated expression of BTK in myeloma cells leads to AKT/WNT/β-catenin-dependent upregulation of key stemness genes (OCT4, SOX2, NANOG, and MYC) and enhanced self-renewal. Enforced transgenic expression of BTK in myeloma cells increased features of cancer stemness, including clonogenicity and resistance to widely used myeloma drugs, whereas inducible knockdown of BTK abolished them. Furthermore, overexpression of BTK in myeloma cells promoted tumor growth in laboratory mice and rendered side population-derived tumors that contained high levels of BTK more sensitive to the selective, second-generation BTK inhibitor, CGI1746, than side population-derived tumors that harbored low levels of BTK. Taken together, these findings implicate BTK as a positive regulator of myeloma stemness and provide additional support for the clinical testing of BTK-targeted therapies in patients with myeloma.