In this final segment of my three part interview from ASCO 2014, my doctor, Dr. Thomas Kipps out of the Moores Cancer Center at UCSD, explains, as only he can, about the competing roles of Bcl-2 and BIM in our malignant B cell clone of chronic lymphocytic leukemia and how ABT-199 resets that balance in our favor in our malignant B cells. “Cancer is not an alien from outer space, cancer is us”
Before you turn off when you hear mention of yet another B cell pathway, please listen to his helpful buttress explanation that explains why this therapy, especially in combinations with other agents, promises a possible cure with no cytotoxic chemotherapy with little collateral damage.
This specific cell death mechanism is particularly active in our malignant B cells. Accordingly, it makes sense as an even more potent target than is blocking B cell communication though the B-cell receptor (BCR). Blocking BCR activity is likely a major mechanism for the outstanding success of the two newly approved targeted oral agents, idelalisib and ibrutinib. ABT-199 works differently. It works directly on the cell’s life and death pathway.
As those who have read my prior post know too well, ABT-199’s very potency is its weakness too. It can kill the cancer so fast there is a risk that the kidneys can’t keep up with the flood of intracellular toxins spilling out of the millions and millions of lysed (broken down) cancer cells. Tragically, at least two deaths have occurred from this tumor lysis syndrome (TLS), and as a result the whole ABT-199 trial strategy was stopped and then revamped, but it’s now back and better.
But when ABT-199 gets out of trials and into the larger community, I worry that TLS may start to reoccur if the education of the community doctors and their patients is not strong enough.
That, my friends, is one of my major goals here and elsewhere: to inform my fellow patients and providers of the changing landscape in managing CLL so we can make smart decisions and get the care we need.
But ABT-199 has gotten some patients to MRD negative status and even allowed durable disease control long after the med is stopped. That is very exciting and appears to be significantly different from the usual results seen with idelalisib and ibrutinib.
In the past I have argued of reducing the tumor burden with Imbruvica or Zydelig, perhaps with a mAB (monoclonal antibody) such as obinituzumab or rituximab, and then cleaning up any residual disease with ABT-199.
I am happy to say that is now a research direction that is being actively pursued.
It’s too early to predict how ABT-199 will fit in the mix, but I predict it will play an important role in the future. The bar already has been set high with the robust responses already seen with the first two approved TKIs. It is not unreasonable to dream that the significant extra kick from ABT-199 or one of the new agents could push us to cure.
So happy to see more research. We must keep pushing for more evolved therapies that offer cure, not just disease control. (Not that I am complaining about the recent advances that have positively changed my life and that of so many other CLL patients.)
But before, we move on, Dr. Kipps has more news for us patients from ASCO 2014.
In the last few minutes of the interview, Dr. Kipps takes a step back and forces us to consider a different perspective on the nature of cancer in general and CLL in particular. He reminds us of cancer’s primitive embryonic nature and how ROR1, an embryonic antigen, might be a major player not just in CLL but in other metastatic cancers such as prostrate or ovary too. Thinking about cancer and CLL in this way opens us the possibility for new avenues of research and therapy. The anti-ROR1 mAB is a step in that direction.
When I saw, Dr. Michael Keating from MDACC at the 2014 AACR hematology meeting, he told me he is betting on ROR1 as the path to cure.
When Drs. Kipps and Keating agree, it is worth listening. And considering a ROR1 trial.
Please enjoy my interview with Dr. Kipps.