The Role of BTK Inhibition in the Treatment of Chronic Lymphocytic Leukemia: A Clinical View

Tambaro, Francesco Paolo; Novellis, Danilo De; Wierda, William G.

doi:10.2147/jep.s265284

Cited by 15 publications

(10 citation statements)

References 109 publications

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“…However, treatment refractoriness and low rates of response to chemoimmunotherapy are frequently seen in patients with aggressive lymphomas such as DLBCL ( 7 , 8 ). Targeted therapies such as B-cell receptor (BCR) signaling inhibitors have improved survival of patients with lymphoid malignancies ( 9 – 11 ), but long-term remission is lacking in a subset of patients and most require prolonged treatment ( 12 ). Immune checkpoint blockade (ICB) is currently being investigated for use in B-cell malignancies but has produced underwhelming results thus far with the exception of Hodgkin’s disease and mediastinal DLBCL ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

et al. 2022

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Regulatory T cells (Tregs) are responsible for maintaining immune homeostasis by controlling immune responses. They can be characterized by concomitant expression of FoxP3, CD25 and inhibitory receptors such as PD-1 and CTLA-4. Tregs are key players in preventing autoimmunity and are dysregulated in cancer, where they facilitate tumor immune escape. B-cell lymphoid malignancies are a group of diseases with heterogenous molecular characteristics and clinical course. Treg levels are increased in patients with B-cell lymphoid malignancies and correlate with clinical outcomes. In this review, we discuss studies investigating Treg immunobiology in B-cell lymphoid malignancies, focusing on clinical correlations, mechanisms of accumulation, phenotype, and function. Overarching trends suggest that Tregs can be induced directly by tumor cells and recruited to the tumor microenvironment where they suppress antitumor immunity to facilitate disease progression. Further, we highlight studies showing that Tregs can be modulated by novel therapeutic agents such as immune checkpoint blockade and targeted therapies. Treg disruption by novel therapeutics may beneficially restore immune competence but has been associated with occurrence of adverse events. Strategies to achieve balance between these two outcomes will be paramount in the future to improve therapeutic efficacy and safety.

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Section: Introductionmentioning

confidence: 99%

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

et al. 2022

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“…Reversible BTKi, such as pirtobrutinib and vecabrutinib, bind BTK non-covalently and do not require C481 to be present [84], thus overcoming this resistance mechanism. They can therefore inhibit BTK in the presence of the C481S mutation, and non-selective reversible BTK-i, including MK1026, may also overcome mutations within PLCG2 [85].…”

Section: Reversible Btk Inhibitorsmentioning

confidence: 99%

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Robak

Witkowska

Smolewski

2022

Cancers

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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications.

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“…On the contrary, pirtobrutinib is a highly selective, reversible BTKi, and could be effective even in the presence of the C481 S mutation of BTK. 68 However, ibrutinib remains the most well studied and predictable BTKi at present. The place of these new drugs in the treatment of HCL and HCL-V remains to be specified.…”

Section: Therapeutic Advances In Hcl and Hcl-v: Focus On Ibrutinibmentioning

confidence: 99%

Updates in hairy cell leukemia (HCL) and variant-type HCL (HCL-V): rationale for targeted treatments with a focus on ibrutinib

Paillassa

Safa

Troussard

2022

Therapeutic Advances in Hematology

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Hairy cell leukemia (HCL) and HCL-like disorders such as hairy cell leukemia variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL) are rare indolent B-cell malignancies. Purine analogs (PNAs), alone or in association with rituximab (R), are the standard of care for HCL in the first-line setting. However, PNAs are toxic and patients may become resistant to these drugs. Therefore, new therapeutic strategies are needed. Several recent in vitro studies highlighted the importance of the interactions between HCL cells and their microenvironment, in particular with bone marrow stromal cells, endothelial cells, and the extracellular matrix. In these interactions, chemokine receptors and adhesion molecules play a major role. Moreover, the importance of signaling pathways, like BRAF, BCR, and CXCR4 has been underlined. Bruton’s tyrosine kinase (BTK) is a fundamental signal transmitter of BCR and CXCR4 in HCL. Preclinical and recent clinical data showed an efficacy of ibrutinib, a BTK inhibitor (BTKi), in HCL and HCL-V. These promising results joined those of other emerging drugs like BRAF or MEK inhibitors and anti-CD22 immunotoxins. Plain Language Summary Bruton’s tyrosine kinase (BTK) inhibitors (BTKi) in hairy cell leukemia (HCL) and variant-type HCL The treatment of hairy cell leukemia (HCL) has changed significantly in recent years. In the first-line settings, treatment with purine analogs (PNAs) with or without anti-CD20 monoclonal antibodies remains the gold standard in 2022. In relapsed/refractory HCL, other drugs are needed: BRAF inhibitors: vemurafenib monotherapy with or without rituximab or dabrafenib in combination with trametinib, an MEK inhibitor (MEKi), as well as the anti-CD22 antibody drug conjugate moxetumomab pasudotox. There are arguments for the use of Bruton’s tyrosine kinase inhibitors (BTKi). Ibrutinib was recently tested in a multisite phase 2 study in 37 patients with either HCL (28 patients: 76%) or HCL-V (nine patients: 24%) including two who were previously untreated. Patients received single-agent ibrutinib at 420 mg daily (24 patients) or 840 mg daily (13 patients) until disease progression or unacceptable toxicity. The overall response rate (ORR) at 32 weeks was 24%, increasing to 36% at 48 weeks and reaching 54% at any time since starting ibrutinib. Seven patients achieved a complete response (CR) as the best response at any time on study, while 13 patients had a partial response (PR) and 10 patients had stable disease (SD). Interestingly, the response rate was not statistically different between HCL and HCL-V patients, suggesting that ibrutinib could be an option in both entities. The estimated 36-month progression-free survival (PFS) was 73% and the estimated 36-month overall survival (OS) was 85%, with no differences between HCL and HCL-V. The frequency of cardiovascular grade 1–2 adverse events (AEs) was 16% for atrial fibrillation; 3% for atrial flutter; 32% for hypertension; and 0%, 3%, and 11%, respectively, for grade ⩾ 3 AEs. Unlike in chronic lymphocytic leukemia (CLL), where the mechanism of action of ibrutinib is well known, the mechanism of action of ibrutinib in HCL appears to be unclear. No mutations were identified in patients with progressive disease, suggesting that the mechanisms of resistance could be different between HCL and CLL. The BTKi that are not yet approved are challenged by the new other targeted treatments.

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The Role of BTK Inhibition in the Treatment of Chronic Lymphocytic Leukemia: A Clinical View

Cited by 15 publications

References 109 publications

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Updates in hairy cell leukemia (HCL) and variant-type HCL (HCL-V): rationale for targeted treatments with a focus on ibrutinib

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