Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

Ponader, Sabine; Burger, Jan A.

doi:10.1200/jco.2013.53.1046

Cited by 104 publications

(81 citation statements)

References 106 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2 Only a small subset of tyrosine kinases in the human genome is predicted to contain a modifiable cysteine residue homologous to cysteine 481 in BTK. 1,3 These include EGFR, HER2, HER4, ITK, BMX, JAK3, TEC, and BLK. 1,3 To what extent inhibition of these kinases contributes to efficacy of ibrutinib is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…1,3 These include EGFR, HER2, HER4, ITK, BMX, JAK3, TEC, and BLK. 1,3 To what extent inhibition of these kinases contributes to efficacy of ibrutinib is unknown. Ibrutinib was approved by the Federal Drug Agency for treatment of B cell malignancies including CLL, mantle cell lymphoma, multiple myeloma, diffuse large B cell lymphoma, and Waldenstrӧm's macroglobulinemia between 2013 and 2015.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Response of renal cell carcinoma to ibrutinib, a bruton tyrosine kinase inhibitor, in a patient treated for chronic lymphocytic leukemia

Hosier

Touma

2017

CUAJ

View full text Add to dashboard Cite

Ibrutinib is a bruton tyrosine kinase (BTK) inhibitor approved for B cell malignancies. Although there are currently two clinical trials evaluating ibrutinib in combination with nivolumab (programmed cell death protein 1, PD-1, inhibitor) or everolimus (mammalian target of rapamycin, mTOR, inhibitor) for metastatic renal cell carcinoma (RCC), there are no reports of RCC (metastatic or non-metastatic) showing response to a BTK inhibitor in humans. Here we report a 22-month clinical response of biopsy-proven RCC to ibrutinib. This is unexpected, given that BTK is not wellimplicated in RCC pathophysiology. We explore a possible mechanism for the response of RCC to ibrutinib through inhibition of interleukin-2-inducible T-cell kinase (ITK) leading to enhanced antitumour immune responses.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Response of renal cell carcinoma to ibrutinib, a bruton tyrosine kinase inhibitor, in a patient treated for chronic lymphocytic leukemia

Hosier

Touma

2017

CUAJ

View full text Add to dashboard Cite

show abstract

“…However, BTK is important in immune tolerance and the potential development of autoimmune antibodies is something that should be monitored in future studies, 97 particularly in light of the observation that ibrutinib may induce immunogenic cell death. 98 In addition, it should be noted that congenital BTK deficiency leads to marked impairment of B-cell development, hypogammaglobulinemia, and recurrent infection, 99 and the effect of chronic drug inhibition on the adult humoral immune system remains unclear. 100 Ibrutinib also targets interleukin-2-inducible kinase within T cells, suggesting possible off-target effects that could contribute to disruption of immune homeostasis in the longer term.…”

Section: Org Frommentioning

confidence: 99%

Perturbation of the normal immune system in patients with CLL

Forconi

Moss

2015

Blood

318

314

View full text Add to dashboard Cite

Immune dysregulation is a cardinal feature of chronic lymphocytic leukemia (CLL) from its early stage and worsens during clinical observation, even in absence of disease progression. Although the mechanisms remain unclear, new insights are emerging into the complex relationship between the CLL clone and its immune environment. T cells are increased in early-stage disease and show progressive accumulation and exhaustion. The mechanisms that drive this expansion may include auto-antigens involved in the original clonal expansion. In addition, chronic viral infections such as cytomegalovirus generate huge virus-specific immune responses, which are further expanded in CLL. Attention is now focused largely on the direct immunosuppressive properties of the tumor. Remarkably, CLL clones often have features of the recently described regulatory B cells producing immunosuppressive IL-10. Better knowledge of the regulatory properties intrinsic to CLL cells may soon become more important with the switch from chemotherapy-based treatments, which trade control of CLL with further impairment of immune function, to the new agents targeting CLL B-cell receptor-associated signaling. Treatment with these new agents is associated with evidence of immune recovery and reduced infectious complications. As such, they offer the prospect of immunologic rehabilitation and a platform from which to ultimately replace chemotherapy

show abstract

“…It also contributes to CLL pathogenesis by being involved in B-cell migration and adhesion. [25][26][27] Ibrutinib is an oral selective and irreversible inhibitor of BTK that acts by forming a bond with cysteine-481 of BTK. The 1 year OS was 90% in the ibrutinib arm and 81% in the ofatumumab arm.…”

Section: Bruton Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Sethi¹,

Reddy²

2017

Oncology &Amp; Hematology Review (US)

View full text Add to dashboard Cite

U ntil recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment. Keywords CLL, novel agents, targeted therapyDisclosure: Tarsheen K Sethi and Nishitha M Reddy have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. In those that meet criteria for treatment, important considerations include: patient age, performance status, comorbidities, and presence of chromosomal aberrations. Recent advancements in the understanding of disease biology have highlighted the importance of several potentially targetable pathways contributing to disease pathogenesis such as aberrant activation of BCR signaling pathway, anti-apoptotic BCL2 pathway, and the role of the microenvironment. These novel agents have expanded the repertoire for patients ineligible for chemoimmunotherapy (CIT) due to age or comorbidities and those with poorly responsive disease (high risk genomics such as del [17p]).This review aims to outline the role of standard CIT, targeted agents and ongoing studies of novel agents defining the present landscape of CLL drug treatment. Currently approved therapies and general tr...

show abstract

Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

Cited by 104 publications

References 106 publications

Response of renal cell carcinoma to ibrutinib, a bruton tyrosine kinase inhibitor, in a patient treated for chronic lymphocytic leukemia

Response of renal cell carcinoma to ibrutinib, a bruton tyrosine kinase inhibitor, in a patient treated for chronic lymphocytic leukemia

Perturbation of the normal immune system in patients with CLL

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Contact Info

Product

Resources

About