PCI-32765 or Ibrutininb and why the great responses in CLL

I almost never just have a strictly medical post, but I thought this was such a clear and concise explanation of how ibrutinib (I better get used to PCI-32765's new name) and GS-1101 (another new name, this time for for CAL-101) that it needed to be shared by those considering one of these new agents for treating their CLL.

Dr. Rai has more experience than anyone in treating CLL and he has no time or tolerance for bogus claims or hype, so I deeply respect his opinion.

That doesn't stop me from questioning his argument in favor of combination therapy.

First. it is too early to know what is best. Dr. Wiestner at the NIH is looking at a single agent therapy and others including Dr Byrd at OSU and Dr. O'Brien at MDACC at combinations.

Second, I worry about powerful chemo selecting out the most refractory clone.

And third and most importantly, I believe that these new small molecules portent a sea change in how we treat CLL with the depth of remission not being the measure of success, but rather the duration of the response.

Let me know what you think.

The original article in Blood can be found here:BLOOD article on ibrutinib.

Thanks to Blood and HemOnc Today.

It is an exciting time in the world of CLL.

9 0Posted March 25, 2012

BTK inhibitor linked to CLL regression

de Rooij MF. Blood. 2012;doi:10.1182/blood-2011-11-390989.

The Bruton’s tyrosine kinase inhibitor PCI-32765 demonstrated inhibitive properties in primary chronic

lymphocytic leukemia, according to recent results.

The researchers based their hypothesis on the premise that small molecule drugs that target the B-cell antigen receptor (BCR) signalosome demonstrate efficacy in B-cell non-Hodgkin’s lymphoma. One such drug, the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765, also demonstrates a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis in CLL. This reduction is reversible upon temporary drug deprivation, according to the researchers↓ The researchers hypothesized that the clinical response induced by PCI-32765 reflects impaired integrin- mediated adhesion and/or migration.

In the current study, it is demonstrated that the drug strongly inhibits BCR-controlled signaling and integrin alpha-4 beta-1–mediated adhesion to fibronectin and vascular cell adhesion molecule-1 of lymphoma cell lines and primary CLL cells, according to the results.

It also has been shown that the drug is an inhibitor to CXCL12-, CXCL13- and CCL19-induced signaling, adhesion and migration of primary CLL cells.

“Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of the malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, resulting in the clinically evident CLL regression,” the researchers concluded.

PERSPECTIVE

Two important new drugs have attracted the attention of colleagues all over the world who treat patients with CLL. Both PCI-32765 and GS-1101 demonstrated an extraordinary level of activity when each was used as a single agent in previously treated CLL patients who had bulky lymphadenopathy, and had relapsed or refractory disease. PCI-32765 is an inhibitor of BTK, while GS-1101 is an inhibitor of PI-3 kinase delta isoform. These kinases are considered to be highly active inhibitors of BCR signalling and chemokine networks. The paper by de Rooij and colleagues provides clear and convincing evidence as to how PCI-32765 actually works. These researchers,by meticulous and disciplined work, demonstrate that this drug acts on the micro- environment of lymph nodes and bone marrow where the leukemic cells can live safely and proliferate, an important mechanism for maintenance and progression of the disease. When exposed to PCI-32765, the leukemic cells can no longer hide in their safe harbors of lymph nodes and bone marrow, and they also can no longer continue to proliferate. Being deprived of adhesion-capabilities, these leukemic cells must, therefore, migrate into the circulating blood. That explains why the bulky lymph nodes shrink in size dramatically and rapidly when the patient starts taking this oral medication. This paper also makes it clear as to why the numbers of lymphocytes in the circulating blood increase equally dramatically,at least initially, while the lymph nodes are shrinking. Finally, this paper explains why it will be important to move from using PCI-32765 as a single agent and toward combining it with a monoclonal antibody or chemotherapy, if a lasting and good-quality remission is the desired objective. The leukemic cells pushed out from the lymph nodes and other tissues are eminently killable by cytocidal agents while they are in the blood circulation, where they no longer have the protective chemokines that allowed them to resist while they resided in the lymph nodes. In my view, this is an important contribution that explains the mechanism of action of the exciting and promising new drugs in the treatment of CLL.

– Kanti Rai, MD

HemOnc Today Editorial Board member Disclosure: Dr. Rai reports no relevant financial disclosures.

Copyright © 2012 HemOnc Today. All rights reserved.