Overview of Clinical Research | <span style="color:#000000;"><span style="font-size:12px;"><span style="font-family:arial,helvetica,sans-serif;">Ibrutinib is an a<span style="font-variant-ligatures: normal; orphans: 2; widows: 2;">gammaglobulinaemia tyrosine kinase inhibitor and an Emt protein-tyrosine kinase inhibitor. It has been granted for the orphan drug status in </span><span style="orphans: 2; widows: 2;">Chronic lymphocytic leukaemia, Mantle-cell lymphoma and Graft-versus-host disease.</span></span></span></span>
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Reference | 1. Drugs. 2015 May;75(7):769-76. doi: 10.1007/s40265-015-0380-3.<br />
Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia.<br />
Kim ES(1), Dhillon S.<br />
Author information:<br />
(1)Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand, [email protected].<br />
Ibrutinib (Imbruvica®) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton/'s tyrosine kinase (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation.<br />
2. Future Oncol. 2014 May;10(6):957-67. doi: 10.2217/fon.14.51.<br />
Ibrutinib: a first in class covalent inhibitor of Bruton/'s tyrosine kinase.<br />
Davids MS(1), Brown JR.<br />
Author information:<br />
(1)Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA.<br />
Ibrutinib (formerly PCI-32765) is a potent, covalent inhibitor of Bruton/'s tyrosine kinase, a kinase downstream of the B-cell receptor that is critical for B-cell survival and proliferation. In preclinical studies, ibrutinib bound to Bruton/'s tyrosine kinase with high affinity, leading to inhibition of B-cell receptor signaling, decreased B-cell activation and induction of apoptosis. In clinical studies, ibrutinib has been well-tolerated and has demonstrated profound anti-tumor activity in a variety of hematologic malignancies, most notably chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), leading to US FDA approval for relapsed CLL and MCL. Ongoing studies are evaluating ibrutinib in other types of non-Hodgkin/'s lymphoma, such as diffuse large B-cell lymphoma and Waldenström/'s macrogobulinemia, in larger Phase III studies in CLL and MCL, and in combination studies with monoclonal antibodies and chemotherapy. Future studies will combine ibrutinib with other promising novel agents currently in development in hematologic malignancies.<br />
3. Drugs Today (Barc). 2014 Apr;50(4):291-300. doi: 10.1358/dot.2014.50.4.2133570.<br />
Ibrutinib for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma.<br />
McDermott J(1), Jimeno A(2).<br />
Author information:<br />
(1)Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. (2)Division of Medical Oncology, Department of Medicine, Developmental Therapeutics Program, University of Colorado School of Medicine, Aurora, Colorado, USA. [email protected].<br />
Ibrutinib is a novel oral tyrosine kinase inhibitor that irreversibly binds and inhibits tyrosine-protein kinase BTK (Bruton tyrosine kinase). BTK has been found to be important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Targeting BTK with ibrutinib has been found to be an effective strategy in treating these malignancies. Phase I clinical testing in non-Hodgkin/'s lymphomas and CLL showed that the drug was extremely well tolerated with no major dose-limiting toxicities and a 54% overall response rate. Subsequently, two phase Ib/II studies were performed on patients with CLL, one in relapsed/refractory CLL and one in previously untreated elderly patients with CLL. Both of these studies continued to show good tolerability of the drug and an overall response rate of about 71% with extended duration of response. Another phase II study using ibrutinib in relapsed/refractory MCL was conducted and also showed that it was well tolerated with an overall response rate of 68% and extended duration of response. Due to these results, the U.S. Food and Drug Administration granted accelerated approval for ibrutinib in November 2013 for patients with MCL who had received at least one prior therapy and in February 2014 for patients with CLL who had received at least one prior therapy. This review will discuss the preclinical pharmacology, pharmacokinetics and clinical efficacy to date of ibrutinib in the treatment of CLL and MCL.<br />
4. Cardiovasc Hematol Agents Med Chem. 2013 Dec;11(4):265-71.<br />
Ibrutinib: a new frontier in the treatment of chronic lymphocytic leukemia by Bruton/'s tyrosine kinase inhibition.<br />
Dias AL, Jain D(1).<br />
Author information:<br />
(1)Division of Hematology and Medical Oncology, James Graham Brown Cancer Center, 529 South Jackson Street, Louisville, Kentucky 40202, USA. [email protected].<br />
Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial myelosuppression and infection. Treatment of CLL is now moving towards targeted therapy. The success of new class of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further search for treatment agents with novel targets to inhibit. The B cell receptor activating pathway involving the Bruton/'s tyrosine kinase (BTK) is crucial in B cell production and maintenance and is an attractive therapeutic target. Ibrutinib is an oral covalent inhibitor of the BTK pathway that induces apoptosis of B cells. Early phase studies with Ibrutinib either as a single agent or in combination regimens have shown promising results with an excellent safety profile in patients with high-risk, refractory or relapsed CLL and elderly treatment-naïve patients. This review summarizes the current knowledge of Ibrutinib in the treatment of CLL.<br />
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