Decrease in total protein level of Bruton’s tyrosine kinase during ibrutinib therapy in chronic lymphocytic leukemia lymphocytes

Cervantes-Gomez, Fabiola; Patel, Viralkumar; Bose, Prithviraj; Keating, Michael J.; Gandhi, Varsha

doi:10.1038/leu.2016.129

Cited by 27 publications

(29 citation statements)

References 9 publications

(16 reference statements)

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“…In the latter disorder, infections are usually caused by encapsulated pyogenic bacteria, including Streptococcus pneumonia, and Haemophilus influenza type B . In this respect, it is interesting to note that Cervantes‐Gomes et al reported a statistically significant time‐dependent decline in the level of total BTK protein in circulating CLL lymphocytes after 2,4 and 12 weeks of continuous standard dose ibrutinib treatment. Recently, Sun et al demonstrated partial reconstitution of humoral immunity and a time related decrease in infection rate in patients with CLL on ibrutinib.…”

Section: Discussionmentioning

confidence: 99%

“…including Streptococcus pneumonia, and Haemophilus influenza type B. 16 In this respect, it is interesting to note that Cervantes-Gomes et al 15 Very recently, it has also been shown in mice, that ibrutinib can inhibit IL2-inducible T cell kinase, a member of the Tec family of tyrosine kinases, which is an important component of T-cell receptor (TCR)-mediated signaling. 18 It is indeed possible that these findings could also partly explain the predisposition to opportunistic infections in patients treated with ibrutinib.…”

Section: Casementioning

confidence: 99%

“…We can presume that the etiology of severe pneumonia during ibrutinib treatment is complex, with drug-induced pneumonitis, The predisposition to infections during therapy with ibrutinib may also be linked to the fact that there are low levels of BTK protein expressed in CLL cells exposed to ibrutinib. 15 In this regard, it is worthwhile recalling that a mutation in the BTK gene, located on the long arm of X-chromosome has been identified as the cause of X-linked agammaglobulinemia-one of the most common primary immune deficiencies encountered in pediatric clinical practice. 16 In the latter disorder, infections are usually caused by encapsulated pyogenic bacteria,…”

Section: Casementioning

confidence: 99%

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Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma

Kreiniz

Bejar

Polliack³

et al. 2017

Hematological Oncology

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In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly "biological drugs." One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients.

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Section: Discussionmentioning

confidence: 99%

Section: Casementioning

confidence: 99%

Section: Casementioning

confidence: 99%

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Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma

Kreiniz

Bejar

Polliack³

et al. 2017

Hematological Oncology

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“…[58] Consistent with these data, total BTK protein was decreased in primary circulating CLL cells obtained from patients undergoing ibrutinib therapy (Figure 2). [95] Furthermore, in CLL patient-derived lymphocytes, the decline was also observed for BTK transcript levels. Ibrutinib attenuates BTK-dependent NF-κB activation, resulting from both BCR[96, 97] and toll-like receptor (TLR)[98] activation.…”

Section: Expert Opinionmentioning

confidence: 97%

“…[29] Student’s t-tests (two-tailed) were performed using the GraphPad Prism6 software (GraphPad Software, Inc. San Diego, CA) to compare values in untreated samples compared to all treated samples and the p values for the comparisons in figure A and figure B are 0.0001 and 0.0003, respectively. Reproduced, with permission, from [95]. …”

Section: Figurementioning

confidence: 99%

Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

Bose

Gandhi

Keating

2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK), is approved in many countries for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) and for previously untreated disease with a 17p deletion and, most recently, as a frontline therapy for CLL. In controlled trials in CLL, ibrutinib produced high response rates and improved survival in both the frontline and relapsed settings. While ibrutinib controls CLL with impressive efficacy, it only infrequently induces complete remissions, particularly of relapsed CLL, and does not eradicate minimal residual disease. Finally, ibrutinib is extremely expensive, has off-target toxicities, and requires indefinite therapy. Areas covered In this article, we provide an overview of the CLL therapeutic landscape and discuss the pharmacokinetic and pharmacodynamic aspects of ibrutinib. Major clinical trials of ibrutinib in CLL are summarized, and its safety profile explored. Expert Opinion Ibrutinib represents a transformative advance in CLL management and has validated BTK as a therapeutic target in this disease, but has some limitations, leading to the emergence of other BTK inhibitors and mechanism-based combination strategies. Given complete BTK occupancy at lower doses of ibrutinib and declining levels of BTK on ibrutinib therapy, lower doses of ibrutinib in CLL are being explored.

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Assessment of ibrutinib scheduling on leukocyte, lymph node size and blood pressure dynamics in chronic lymphocytic leukemia through pharmacokinetic‐pharmacodynamic models

Ibrahim

Karlsson

Friberg

2023

CPT Pharmacom & Syst Pharma

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Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor for treating chronic lymphocytic leukemia (CLL). It has also been associated with hypertension. The optimal dosing schedule for mitigating this adverse effect is currently under discussion. A quantification of relationships between systemic ibrutinib exposure and efficacy (i.e., leukocyte count and sum of the product of perpendicular diameters [SPD] of lymph nodes) and hypertension toxicity (i.e., blood pressure), and their association with overall survival is needed. Here, we present a semi‐mechanistic pharmacokinetic‐pharmacodynamic modeling framework to characterize such relationships and facilitate dose optimization. Data from a phase Ib/II study were used, including ibrutinib plasma concentrations to derive daily 0–24‐h area under the concentration‐time curve, leukocyte count, SPD, survival, and blood pressure measurements. A nonlinear mixed effects modeling approach was applied, considering ibrutinib's pharmacological action and CLL cell dynamics. The final framework included (i) an integrated model for SPD and leukocytes consisting of four CLL cell subpopulations with ibrutinib inhibiting phosphorylated Btk production, (ii) a turnover model in which ibrutinib stimulates an increase in blood pressure, and (iii) a competing risk model for dropout and death. Simulations predicted that the approved dosing schedule had a slightly higher efficacy (24‐month, progression‐free survival [PFS] 98%) than de‐escalation schedules (24‐month, average PFS ≈ 97%); the latter had, on average, ≈20% lower proportions of patients with hypertension. The developed modeling framework offers an improved understanding of the relationships among ibrutinib exposure, efficacy and toxicity biomarkers. This framework can serve as a platform to assess dosing schedules in a biologically plausible manner.

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Decrease in total protein level of Bruton’s tyrosine kinase during ibrutinib therapy in chronic lymphocytic leukemia lymphocytes

Cited by 27 publications

References 9 publications

Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma

Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma

Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

Assessment of ibrutinib scheduling on leukocyte, lymph node size and blood pressure dynamics in chronic lymphocytic leukemia through pharmacokinetic‐pharmacodynamic models

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