Metabolic and toxicological considerations of Bruton's tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

INTRODUCTION: Bruton tyrosine kinase inhibitors (BTKi) have been used for the management of human diseases since the approval of the first-in class agent, ibrutinib, by the Food and Drug Administration in 2013 for the treatment of patients with mantle cell lymphoma (MCL). Ibrutinib is a covalent inhibitor along with second-class BTKis: acalabrutinib and zanubrutinib. These well-tolerated agents have transformed the treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). A new class of these inhibitors, non-covalent, might become an answer to the emerging resistance by avoiding the sustained contact with the kinase binding domain. AREAS COVERED: This article examines the chemical composition, mechanism of action, metabolic characteristics, and potential toxicity of inhibitors targeting Bruton tyrosine kinase. A comprehensive search was conducted across English-language articles in PubMed, Web of Science, and Google Scholar. EXPERT OPINION: Bruton tyrosine kinase inhibitors have greatly enhanced the armamentarium against lymphoid malignancies including CLL/SLL. Their future lies in the choice of appropriate patients who will benefit from the treatment without significant adverse reaction. Combination chemotherapy-free fixed-duration regimens with targeted molecules will allow for MRD-driven approach in patients with CLL/SLL in the near future.

Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. AREAS COVERED: This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English. RESULTS/CONCLUSION: PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies, including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. EXPERT OPINION: The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.

The preclinical discovery and development of orelabrutinib as a novel treatment option for B-cell lymphoid malignancies.

INTRODUCTION: Bruton's tyrosine kinase (BTK) inhibitors have recently been approved for clinical use against several B-cell indolent lymphoid malignancies, both as single agents or in combination. One second-generation BTK inhibitor that is being developed for the treatment of B-cell hematological malignancies, as well as for autoimmune disorders, is orelabrutinib. AREAS COVERED: This paper reviews recent developments in the use of orelabrutinib against B-cell indolent lymphoid malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia and central nervous system lymphoma. Google Scholar and PubMed were initially searched for articles, and the corpus of articles was broadened by reviewing the references of the identified papers. All were in English. The corpus comprised papers from 2016 to April 2023. In addition, a manual search was performed of conference proceedings from the last five years of The American Society of Hematology, American Society of Clinical Oncology and the European Hematology Association. EXPERT OPINION: Orelabrutinib is an active drug in indolent and aggressive B-cell lymphoid malignancies. It demonstrates high selectivity, good efficacy and an excellent safety profile. Nevertheless, further clinical trials are required to optimize its use. In addition, several other highly selective BTK inhibitors are being examined in early-phase studies.

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions.

Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a next-generation irreversible inhibitor of Bruton's tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies.

Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studies have led to the development of proteasome inhibitors, which have advanced into drugs (such as bortezomib) used in the treatment of certain hematological tumors, including multiple myeloma. New therapeutic options have been studied making use of the so-called proteolysis-targeting chimeras (PROTACs), that bind desired proteins with a linker that connects them to an E3 ubiquitin ligase, resulting in proteasomal-targeted degradation. This review examines the mechanisms of protein degradation in the cells of the hematopoietic system, explains the role of dysfunctional protein degradation in the pathogenesis of hematological malignancies, and discusses the current and future advances of therapies targeting these pathways, based on an extensive search of the articles and conference proceedings from 2005 to April 2022.

Acalabrutinib: a bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia.

INTRODUCTION: The first-in-class Bruton tyrosine kinase (BTK), ibrutinib, demonstrated remarkable activity in chronic lymphocytic leukemia (CLL). However, its toxicity profile renders it potentially inappropriate for use in patients with bleeding or cardiovascular disorders. In response to the high demand for a safer and efficient BTK inhibitor, with improved toxicity profile, acalabrutinib as a second-generation irreversible BTK inhibitor has been approved for the treatment of CLL. AREAS COVERED: This review examines the activity of acalabrutinib in treating treatment-naïve and relapsed refractory CLL and its toxicity profile when compared to ibrutinib and other drugs. It will examine the outcomes of the ELEVATE-TN, ASCEND, and ELEVATE-RR studies in detail, with a particular focus on the safety and efficacy of acalabrutinib. The strengths and weaknesses of this drug will be highlighted and future directions for research will be identified. EXPERT OPINION: In patients with CLL, acalabrutinib demonstrates a superior safety profile than ibrutinib and similar activity. In the first direct comparison of acalabrutinib with ibrutinib in relapsed/refractory CLL, acalabrutinib was found to demonstrate non-inferior progression-free survival, with fewer cardiovascular adverse events.

Advances in the pharmacotherapeutic options for primary nodal peripheral T-cell lymphoma.

INTRODUCTION: Peripheral T cell lymphomas (PTCL) are a group of heterogenous hematologic malignancies derived from post-thymic T lymphocytes and mature NK cells. Conventional chemotherapy does not guarantee a good outcome. AREAS COVERED: The article summarizes recent investigational therapies and their mechanism of action, as well as the pharmacological properties, clinical activity, and toxicity of new agents in the treatment of primary nodal PTCLs. The review scrutinized papers included in the MEDLINE (PubMed) database between 2010 and October 2020. These were supplemented with a manual search of conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, and American Society of Clinical Oncology. Further relevant publications were obtained by reviewing the references from the chosen articles. EXPERT OPINION: PTCLs have proved difficult to treat and investigate because of their rarity. Studies of aggressive lymphoma, including a small proportion of T-cell lymphomas, found that any benefit from intensified traditional chemotherapy in patients with PTCL is accompanied by increased toxicity. However, the management of PTCL is beginning to change dramatically, thanks to the use of more sophisticated agents targeting the mechanisms of disease development.

Associations of ficolins and mannose-binding lectin with acute myeloid leukaemia in adults.

We investigated clinical associations of ficolins and mannose-binding lectin (MBL) in 157 patients suffering from acute myeloid leukaemia (AML). Concentrations of ficolin-1, ficolin-2, ficolin-3 and MBL (before chemotherapy) in serum were determined as were selected polymorphisms of the corresponding genes (FCN1, FCN2, FCN3 and MBL2). The control group (C) consisted of 267 healthy unrelated individuals. Median level of ficolin-1 in patients was lower (p < 0.000001) while median levels of ficolin-2, ficolin-3 and MBL were higher (p < 0.000001, p < 0.000001 and p = 0.0016, respectively) compared with controls. These findings were generally associated with AML itself, however the highest MBL levels predicted higher risk of severe hospital infections (accompanied with bacteremia and/or fungaemia) (p = 0.012) while the lowest ficolin-1 concentrations tended to be associated with prolonged (> 7 days) fever (p = 0.026). Genotyping indicated an association of G/G homozygosity (corresponding to FCN1 gene - 542 G > A polymorphism) with malignancy [p = 0.004, OR = 2.95, 95% CI (1.41-6.16)]. Based on ROC analysis, ficolin-1, -2 and -3 may be considered candidate supplementary biomarkers of AML. Their high potential to differentiate between patients from non-malignant controls but also from persons suffering from other haematological cancers (multiple myeloma and lymphoma) was demonstrated.

Glasdegib in the treatment of acute myeloid leukemia.

Pharmacologic inhibition of the Hedgehog pathway significantly enhanced the sensitivity of leukemic cells to cytotoxic drugs. Glasdegib (PF-04449913; DAURISMO™) is a potent and selective oral inhibitor of the Hedgehog signaling pathway with clinical activity in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), particularly in combination with chemotherapy. The results of Phase Ib/II studies evaluating safety and efficacy of glasdegib combined with chemotherapy in previously untreated patients with AML or high-risk myelodysplastic syndrome have recently been published. In the BRIGHT AML 1003 study, glasdegib in combination with low-dose cytarabine (LDAC) was well tolerated and demonstrated a significant 54% reduction in mortality compared with LDAC for AML patients. In 2018, the US FDA approved glasdegib in combination with LDAC for the treatment of newly diagnosed patients with AML who are 75 years old or older or who have co-morbidities that preclude use of intensive induction chemotherapy.

Safety and Tolerability of Antibody-Drug Conjugates in Cancer.

Antibody-drug conjugates are monoclonal antibodies attached to biologically active drugs through chemical linkers that deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. Currently, there are about 110 ongoing studies implementing antibody-drug conjugates in the treatment of multiple human malignancies. Antibody-drug conjugates carry a feature of the specificity of a monoclonal antibody and the anti-neoplastic potential of a cytotoxin. The first antibody-drug conjugate was approved in 2001, and the field of antibody-drug conjugates has expanded since then with three more antibody-drug conjugates being added to the market. The complex structure of the antibody-drug conjugate poses a challenge in designing a clinically adequate molecule. Antibody-drug conjugates are usually well tolerated with some predictable adverse reactions, as well as new medical issues, that need careful approach. This review provides an outline of the current status of the efficacy and safety of antibody-drug conjugates in malignant diseases.

Emerging antibody-drug conjugates for treating lymphoid malignancies.

INTRODUCTION: Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects. Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.