Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia

Mulder, Tom A.; Peña-Pérez, Lucía; Berglöf, Anna; Meinke, Stephan; Estupiñán, H. Yesid; Heimersson, Kia; Zain, Rula; Månsson, Robert; Smith, C. I. Edvard; Palma, Marzia

doi:10.1097/hs9.0000000000000564

Cited by 17 publications

(18 citation statements)

References 71 publications

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“…Patients with chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency [ 1 , 2 ] that does not exclude novel precision therapeutics such as ibrutinib [ 3 , 4 ]. Two early international surveys reported that hospital-admitted Covid-19 patients with CLL had a high fatality rate [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B- and T-cell immunity during 13 months in consecutive patients

et al. 2021

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We studied clinical and immunological outcome of Covid-19 in consecutive CLL patients from a well-defined area during month 1–13 of the pandemic. Sixty patients (median age 71 y, range 43–97) were identified. Median CIRS was eight (4–20). Patients had indolent CLL ( n = 38), had completed ( n = 12) or ongoing therapy ( n = 10). Forty-six patients (77%) were hospitalized due to severe Covid-19 and 11 were admitted to ICU. Severe Covid-19 was equally distributed across subgroups irrespective of age, gender, BMI, CLL status except CIRS ( p < 0.05). Fourteen patients (23%) died; age ≥75 y was the only significant risk factor (p < 0.05, multivariate analysis with limited power). Comparing month 1–6 vs 7–13 of the pandemic, deaths were numerically reduced from 32% to 18%, ICU admission from 37% to 15% whereas hospitalizations remained frequent (86% vs 71%). Seroconversion occurred in 33/40 patients (82%) and anti-SARS-CoV-2 antibodies were detectable at six and 12 months in 17/22 and 8/11 patients, respectively. Most (13/17) had neutralizing antibodies and 19/28 had antibodies in saliva. SARS-CoV-2-specific T-cells (ELISpot) were detected in 14/17 patients. Covid-19 continued to result in high admission even among consecutive and young early- stage CLL patients. A robust and durable B and/or T cell immunity was observed in most convalescents.

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Section: Introductionmentioning

confidence: 99%

Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B- and T-cell immunity during 13 months in consecutive patients

et al. 2021

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“…Proliferating T cells and expression of activation markers and immune checkpoints (PD-1, CTLA-4) also decreased both after treatment with ibrutinib ( 64 , 65 , 69 ), acalabrutinib ( 68 ) and zanubrutinib ( 53 ), also likely reflecting the decrease in tumor burden.…”

Section: Immunomodulatory Effects Of Btk Inhibitorsmentioning

confidence: 93%

“…The effects of ibrutinib on the T-cell compartment have been reviewed by Mhibik et al (63). Even if the findings regarding the changes in T-cell numbers, including major subsets, during ibrutinib treatment have been controversial, with both reports on decrease (64,65) and increase (66), the available evidence seems to point out that T cells decrease in parallel with the reduction of the tumor burden (64,65,67). Indeed, T cells are usually abnormally elevated in R/R CLL patients (61), chronically activated by tumor antigens.…”

Section: Effects On Adaptive Immunitymentioning

confidence: 99%

BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects

2021

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Bruton´s tyrosine kinase (BTK) inhibitor (BTKi)s block the B-cell receptor (BCR) signaling cascade by binding to the BTK enzyme preventing the proliferation and survival of malignant and normal B cells. During the past decade, the clinical use of BTKis for the treatment of B-cell malignancies has exponentially grown, changing the treatment landscape for chronic lymphocytic leukemia (CLL) in particular. At present, three different covalent BTKis, ibrutinib, acalabrutinib and zanubrutinib, are FDA-approved and many new inhibitors are under development. Despite having remarkable selectivity for BTK, the first-in-class BTKi ibrutinib can also bind, with various affinities, to other kinases. The combined inhibition of BTK (“on-target” effect) and other kinases (“off-target” effect) can have additive or synergistic anti-tumor effects but also induce undesired side effects which might be treatment-limiting. Such “off-target” effects are expected to be more limited for second-generation BTKis. Moreover, the blockade of BCR signaling also indirectly affects the tumor microenvironment in CLL. Treatment with BTKis potentially impacts on both innate and adaptive immunity. Whether this affects infection susceptibility and vaccination efficacy requires further investigation. Here, we summarize the available knowledge on the impact of BTKis on the immune system and discuss the possible clinical implications. Indeed, a deeper knowledge on this topic could guide clinicians in the management and prevention of infections in patients with CLL treated with BTKis.

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“…Sequence alignment of BTK and Src family kinases and screening of first-generation inhibitors that bind to the ATP-site revealed that C481 in BTK could act as a nucleophile and form a covalent bond with an inhibitor ( 30 ). This led to the birth of ibrutinib, the first irreversible BTK inhibitor, which is approved as treatment for several B-cell malignancies ( 25 , 31 ).…”

Section: Btk Inhibitorsmentioning

confidence: 99%

Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors

Zain

Vihinen

2021

Front. Immunol.

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Low-molecular weight chemical compounds have a longstanding history as drugs. Target specificity and binding efficiency represent major obstacles for small molecules to become clinically relevant. Protein kinases are attractive cellular targets; however, they are challenging because they present one of the largest protein families and share structural similarities. Bruton tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, has received much attention as a promising target for the treatment of B-cell malignancies and more recently autoimmune and inflammatory diseases. Here we describe the structural properties and binding modes of small-molecule BTK inhibitors, including irreversible and reversible inhibitors. Covalently binding compounds, such as ibrutinib, acalabrutinib and zanubrutinib, are discussed along with non-covalent inhibitors fenebrutinib and RN486. The focus of this review is on structure-function relationships.

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Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia

Cited by 17 publications

References 71 publications

Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B- and T-cell immunity during 13 months in consecutive patients

Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B- and T-cell immunity during 13 months in consecutive patients

BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects

Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors

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