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Agents that Target Disease Pathways >  BtK Inhibitors

Last update: 02/05/2015

 
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What is Bruton's tyrosine kinase (BTK)?

As we understand it, Bruton's tyrosine kinase (Btk) is a pathway that controls the function of the B cell antigen receptor (BCR), the "business end" of the mature b-cell

The BCR is the receptor that binds to pathogens (bacteria, virus ...) that invade the body. In a sense, the BCR is the b-cell's reason for being ... what it does for a living.   Picture it: cellsignal.com

In the illustration, the Ag represents an antigen bound to the B-Cell Receptor, and the Bruton's tyrosine kinase (Btk) is downstream of this molecule.

When the b-cell antigen receptor binds to an antigen a cascade of signals take place within the cell, which promotes the prolonged survival of the cell and cell cycle progression.  (Just what we don't want to happen when the b-cell is abnormal - a lymphoma cell.)

Drugs that bind to BTK may preferentially target mature b-cells (not skin cells, etc) preventing the BCR from working, and in turn limiting the survival of these cells.

Thus, btk-inhibitors may prove to be another important way to manage b-cell lymphoma, or improve the cure rate, with less toxicity than less-specific chemotherapy drugs.  The BTK inhibitors may be used as a single agent or with standard therapies -- similar to how Rituxan is used today.

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Abstract Title: Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase
http://www.springerlink.com/content/j03j1873301k3460/ 


Agents targeting btk in clinical phase testing   

Find for Class of therapy Ibrutinib  
PubMed Query of
Ibrutinib

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Reports
 

DLBCL Relapsed

ClinicalTrials.gov: for Relapsed/ Refractory DLBC Lymphoma
Ibrutinib + Lenalidomide, With and Without Rituxan
http://1.usa.gov/1dZS4a3  >   Site: Mid-Ohio Oncology/ Hematology
 

 
 

CLL/SLL Relapsed or Refractory

Comparing: Bendamustine-Rituxan (B-R) to B-R with Ibrutinib

 

 
 

Other trials of interest

 

 


In the News

* 2015: Experts discuss Initiation and Discontinuation of Ibrutinib From 
* Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes http://1.usa.gov/16ud6gm 

This technical paper describes an off-target effect of ibrutinib that could, possibly, limit its long term use (as noted by Dr. Bryd in the discussion that follows). The off-target effect on t-cells might also further explain its efficacy as touched on in this snip:

This report establishes a previously unidentified immunomodulatory mechanism of action for ibrutinib that has the potential to expand its antitumor applications. Aside from T-cell malignancies for which ITK acts as a driver, it is well appreciated that tumors develop a prosurvival niche enhanced by Th2-polarized CD4 T cells.1,2 In leukemia, these cells provide constitutive IL-4, IL-6, and CD40L stimulation, driving the expansion of disease.44
* ASH 2012 Paper:
The Brutonís Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma http://bit.ly/VkVB9p
* Approval for CLL -  Medscape 2014:
FDA Sends Valentine to CLL Patients (Cheson video) http://bit.ly/1cXxfYB
* Patient Power 2013:   Video of Dr Sharman discussing Ibrutinib and other options
Promising Advances in Treating Mantle Cell Lymphoma http://bit.ly/14n6PRr

* Dr Sharman 2013:
Ibrutinib gets first approval in Mantle Cell Lymphoma http://bit.ly/1aTSqP9

*Onclive 2013:
FDA Approves Ibrutinib for Mantle Cell Lymphoma http://bit.ly/1bEeoSQ

*The Street 2013
Pharmacyclics' Lymphoma Drug Receives FDA Approval. Cost: $130,000 Per Year! http://bit.ly/1j53I1S
* Picture it:  B-cell receptor and related pathways:





 

 

Find Clinical reports:

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Google Scholar Search on Btk inhibitors

Lymphomas that arise from mature B-cells

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B-cells arise from stem cells in the bone marrow.  These specialized immune cells express different features as they mature (on there cell surface, but also internally). 

This provides opportunities to target lymphomas that arise from defective mature b-cells (such as follicular and DLBCL).   Therapy that binds such targets will not affect stem cells or immature b-cells - allowing for the restoration of this part of the immune system when the therapy is discontinued. 

Rituxan is an example of a therapy that is specific to mature b-cells, as it targets cd20, which is not expressed on immature b-cells as shown in the image that follows:

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Picture it:  b-cell maturation on nature.com.

In the illustration, the arrows show where CD20 and other surface markers on mature b-cells are first expressed.
 

Clinical trials for PCI-32765
(Ibrutinib) targeting Bruton's tyrosine (Btk):

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http://1.usa.gov/v6ZncS 

Related Articles and information:

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* Ibrutinib: full prescribing information (Label)
From accessdata.fda.gov: http://1.usa.gov/1fkjyqY 
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Immunology: 3.2.1 Stages of B lymphocytes maturation  wenliang.myweb.uga.edu
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Combined deficiencies in Bruton tyrosine kinase and phospholipase Cγ2 arrest B-cell development at a pre-BCR+ stage  http://bloodjournal.hematologylibrary.org/content/109/8/3377.full


 
 
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