Oral drugs that inhibit the tyrosine kinase enzymes that are part of signalling molecules in various cancer cells (as well as normal cells in some cases) are the current rage in oncology drug development. In chronic myelogenous leukemia (CML) treatment has been revolutionized with this approach to inhibiting an abnormal signalling protein that occurs in this type of leukemia. First, the tyrosine kinase inhibitor (TKI) imatinib (Gleevec) was approved in 2001 and then at least 4 more approved in following years, the most recent being ponatinib approved in December 2012.
In CLL there are signalling pathways within the B cell that also have tyrosine kinase proteins for which there have been oral drugs developed. Two are in phase III trials, ibrutinib and idelasib, both of inhibit signalling proteins in B cell receptor network. The B cell receptor or BCR is an antibody like molecule that when stimulated leads to B cell multiplication, OK for normal B cells, bad when leukemia cells do so. Here is a very complex diagram of the BCR pathway:
ibrutinib inhibits the BTK protein and idelasib the P13K (see black boxes in diagram above).
See a video of interview by Dr Brian Koffman, a fellow MD and CLL survivor, of Dr Thomas Kipps about drugs that effect BCR in development for CLL.
Not as far in development is GS-9973 which inhibits the protein SYK (also boxed in above). There is an intriguing phase II trial that will evaluate the combination of idelasib and GS-9973 that is not yet recruiting patients. The idea of using two inhibitors is clearly aiming for a synergistic effect or perhaps bypassing any mutations in the proteins that would develop during therapy and lead to proteins resistant to one of the drugs.
Another signalling protein network involves apoptosis, or cell death. The family of proteins to which Bcl-2 belongs inhibit the sequence of signals that lead to apoptosis. See the diagram below, the boxed areas are where Bcl-2 is thought to work on mitochondria, inhibiting the signal that leads to cell death.:
By inhibiting Bcl-2, apoptosis of leukemic cells could proceed. The drug furthest in development is ABT-199 which has had a temporary setback with a suspension of recruitment for early phase trials due to several deaths from tumor lysis syndrome. The company developing the drug, Abbvie, has stated
"Previous and current trials have shown that dose escalation methods can control tumor lysis syndrome and we have every expectation that the trials will come off of clinical hold and that we will be able to initiate Phase 3 trials in 2013, as planned."
See the video interview of Dr Kipps on Bcl-2 in CLL.
So how might one of these drugs help me? Well I am clearly not in remission, the rituximab-high dose methylprednisone only shrinking my quite large left cervical node temporarily. Although I don't have peripheral lymphocytosis and my marrow is recovering with reg(ard to platelets and RBC (see prior posts on this blog), see the ginormous node which continues to increase now only about 9 days after finishing the last cycle of HDMP:
Since my other palpable nodes are not as rapidly growing, I of course worry about Richter's transformation, but I always worry about that. Am getting a CT scan in several weeks to see how nodes are doing internally but if I don't have Richter's I clearly need more treatment. I am quite interested in the phase II trial of the agents in combination noted above. I plan to email the investigator to inquire as to where the trial is being done, hopefully one will be reasonably close to home. I think since my other option, the CAR T cell study has not been formally offered to me, I have to keep my options open......
