ASCO 2014: Dr. Kipps on ABT-199 and more on CLL (chronic lymphocytic leukemia): "Cancer is not an alien from outer space, cancer is us"

More mural work from my son, Ben Koffman

In this final segment of my three part interview from ASCO 2014, my doctor, Dr. Kipps out of the Moore Cancer Center at UCSD, explains as only he can about the competing roles of Bcl-2 and BIM in our malignant B cell clone and how ABT-199 resets that balance in our favor in our malignant B cells.

Here are links to part one and part two of the same interview. They will help set up and give perspective on this longer final segment.

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 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 than revamped, but it's now back and better.

In other posts, I discussed one tragic death that happened in the trial and argue strongly then that its development be continued and I am so glad that has happened.

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 of so many other CLL patients.)

Later I will comment on the recently announced combination of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo) and the oral BTK inhibitor ibrutinib (Imbruvica) in a phase I/II trial for patients with non-Hodgkin lymphoma (NHL). This is another promising and bold path that has me pretty excited.

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 AACR hematology meeting last month in Philadelphia,  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.



More soon. (By the way, my ASCO 2014 goatee is long gone.)

This is my crazy season of traveling and teaching, so please forgive my tardiness in posting.

I will be at the LRF conference this Saturday, Oct. 25, 2014 in Manhattan Beach, so please join me and say hello. If you have never attended a LRF conference, they are worthwhile on so many ways. Do come and learn and meet fellow patients.

We are all in this together.

Personal Update on my CLL (Chronic Lymphocytic Leukemia): The Good News

It's been a while since I posted on my personal medical news.

Today in Columbus, it was all good. CBC was happily and boringly normal. My Hgb still shows that I am no longer anemic. My ALC (lymphocytes) is 1.4 which is actually a bit high for me, but certainly a comforting level.

My ANC (neutrophils) was healthy. My platelets are a bit higher than normal again, but that is to be expected due my splenectomy. The spleen gleans the aging and decrepit platelets, so counts are higher when it's missing. I will take high platelets any day over the terrors of single digit counts when my ITP was raging. By the way, the accepted wisdom is that the high platelets associated with a splenectomy do not increase the risk of a blood clot, but ironically ITP which ravages the platelets does. You can both hemorrhage and thrombose with the same disease. Seems inflammation is the enemy. I refer you to the 19th century wisdom of Virchow's triad, a trusted nugget carried in the brain of all medical students. 

More on this particular topic soon with some personal revelations, but that is for another post.

My blood chemistries show my liver and kidneys are happy and healthy. The advantages of a vegan lifestyle.

Dr. Byrd would not agree to skipping my next CT scan in three months. The very few late relapses on ibrutinib that he has seen after 24 months (my two year anniversary of living with the TKI magic of ibrutinib aboard will be at 9:30 AM EST on May 7, 2014) are often subtle and begin in the nodes. With my pesky abdominal nodes, that does seem prudent despite my aversion to more diagnostic "radiation therapy". Getting the scan at the newer CT at OSU's Martha Morehouse may cut the rads by as much 60%.

Most relapses occur between 12 and 24 months, so my period of higher risk is thankfully coming to an end. 

Still my clonal instability and my small subclone of 17p deleted cells keeps me forever on alert.

What we really need is a trial for the many patients such as myself that are doing very well on ibrutinib, but are not in a complete remission (CR). How about adding in a PI3K inhibitor such as idelalisib or one of the newer ones following in its footsteps. Hit the cancer clone on two pathways at once. A pincer move. A classic chemotherapy technique, but instead on chemo, we box off the cancer with focused therapies. Next add a potent third generation monoclonal antibody (mAb) such as obinutuzumab once the rascally clonal B cells have been released from the nodes and marrow out into the open spaces of the blood stream where they are easy picking for the antibody. Finally, we add something to mess with Bcl-2, say ABT-199. All this done in a carefully orchestrated and timed dance to maximize efficacy and dodge tumor lysis (TLS) by adding the ABT-199 as the final coup de grâce to make sure the beast will never rise again, but also when the tumor load is low so the risk of TLS is mitigated.

You can't get to cure without first passing by CR and MRD (minimal residual disease) negative.

For me, this is not a theoretical discussion. This is my blood and marrow and proliferative centers in my node that are at stake.

The same applies to many others that are in similar circumstances with ibrutinib and other TKIs.

It may even make long term financial sense in that it may also be a way to limit the duration of therapy with this initial treatment intensification, but with a predicted end of treatment baked into the plan.

I don't want to wait until it's too late so I am hoping such a trial may come to pass, speedily, in my time.  

These and similar concepts are beginning to percolate out there.

What do you think?

I am wondering about bouncing such a plan off the powers that could make it happen. Right now it is a small population that would qualify for such a trial, but our numbers are growing fast.

Please give me your feedback.

"You may say I'm a dreamer, but I am not the only one."

More news, personal and general soon.

I wish a meaningful Passover to all my Jewish friends. May we all leave our personal Pharaohs behind and cross dry shod into the promised land.

iwCLL 2013: Dr. Tom Kipps Discusses the Changing Role of Chemo-immunotherapy in CLL and the New Role of BCL-2 Blockers

Dr. Tom Kipps is my personal CLL physician and was announced the winner of the prestigious Binet-Rai award for his contribution to CLL research at the iwCLL 2013 meeting.

This interview from a few months ago provides important background to help understand and get perspective on the great news from ASH 2013 on ABT-199 that I will be reporting and analyzing here soon with the help of the many of the doctors who actually lead the research.

In the first part of this interview with Dr. Kipps in Cologne, Germany, he first lays out some of the groundwork of when not to use chemotherapy.

Next, he gives us some of the history of how BCL-2 blockers work. I love his cathedral and buttress analogy especially after walking through the beautiful and delicate cathedral in Cologne. It seems like only yesterday that I was there working at the iwCLL meeting and visiting the sights when I got a break.

Cologne Cathedral

Next he explains the risks of tumor lysis syndrome. Two deaths about a year ago that halted the trial for months. But it has restarted on was reported on at ASH.

And he touches us on the tricky area of how and when can we stop these meds.



Due to a technical glitch, the final part of Dr. Byrd's interview will have to wait.

I will be mixing videos and analysis from iwCLL and ASH over the next several weeks. So much to share.

ASCO 2013: Dr. Sharman on The Biology of CLL being Cracked with a Therapeutic Renaissance Underway

At the ASCO 2013 in Chicago, I had a chance to catch on camera some of the enthusiasm and optimism of Dr. Sharman.

Dr. Sharman is the director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, and a very creative and visionary doctor and a great blogger. His posts are always worth reading.

In this  interview, he clearly outlines the rationale of using the new small molecules that blocks BCR (b-cell receptor) or Bcl-2 (b-cell lymphoma-2).

He shares some of the development of third generation mAbs (monoclonal antibodies) such as obinutuzumab to turn on the immune system.  We learned in my earlier ASCO post with Dr. Wierda, immunotherapy, namely an allogeneic stem cell transplant is the only proven cure on CLL. And we have strong data from the German trial and others that adding a mAb such as rituximab to FC makes the chemotherapy better, so building a better antibody is an important step forward .

The swelling number of promising new molecules and treatment options needs to be met with an reciprocal swelling number of volunteers for clinical trials to keep the renaissance alive.

Are we already in a therapeutic renaissance for CLL?  I believe we are just in the very earliest stages of the coming change to the treatment paradigm, but we need many more bright lights to guide our way and that will only be produced by the hard work of the bench scientists and the valour of the volunteers  who enroll in well designed and patent friendly clinical research. Only then will we able to say that we have turned the corner on the "dark ages" of CLL

Thanks again to Andrew Schorr and the great team at Patient Power for helping make these interviews possible.

More soon.

ASH 2012: Dr. Tom Kipps Explains why Understanding CLL Biology Helps us Focus Therapies: Bcl-2 and ABT-199; as well as my Reporting on the Suspended Trials

This is the first of a four part interview with my doctor, Dr. Tom Kipps, where he unpacks for us the complexities of why Bcl-2 is such an attractive target in CLL.

This is not a theoretical construct, but is directly pertain to a powerful drug that is in clinical trials right now: ABT-199. That power is a double edged sword and I discuss the recent news about the trial suspensions later in this post.

It turns out that of the all the B-cell cancer, CLL is guilty of the greatest overproduction of this Bcl-2 which is a strong cellular anti-suicide messenger. Twin that with the contravening fact that CLL cells also overproduce the powerful pro-apoptotic (programmed cell death) compound BIM. But BIM is held in check by the excess Bcl-2.  Block Bcl-2 and then the BIM goes bam and the cancer cell suicides.

Vey good.

That is where ABT-199 comes in. But I will let Dr. Kipps explains.



Now all this power to take the safety off the suicide bomber inside every CLL cell comes with a heavy cost. If it is too effective, especially in someone with a high tumor burden (read very high lymphocyte count and huge nodes) and /or there is a significant dose escalation, the cell death toll can exceed the body's ability to cope with all the waste produced by the broken down cells. This is the dreaded tumor lysis syndrome( see this nice explanation by Dr. Sharman), and it can not only kill the patient, it can kill the development of a life saving drug.

Very bad.

I have waited until there was a reliable public source for confirmation before posting this information on my blog and I got it today from Bloomberg news.

I quote:

AbbVie Inc., the drug company that split off from Abbott Laboratories at the start of the year, suspended five studies on its experimental leukemia and lymphoma medicine after two patient deaths.

The patients died from tumor lysis syndrome, said Tracy Sorrentino, a spokeswoman for North Chicago, Illinois-based AbbVie. The complication stems from the rapid destruction of malignant cells after treatment that can trigger acute kidney failure. It occurs most often with large tumors such as those found in leukemia and lymphoma patients, according to the National Institutes of Health. 

They continue:

“We have every expectation that these trials will come off the partial clinical hold and we’ll be able to initiate Phase 3 trials in 2013 as planned,” she said. “ABT-199 is a highly- potent agent and can result in the tumors reducing really quickly,” she said. “We are working to refine the dose.”

After the complication was discovered, AbbVie and its partner, Roche Holding AG, suspended the dose- escalation portion of the studies to determine the amount of drug that is safest and most effective, Sorrentino said. The risk stems from the drug’s potency and can be managed if the dose is carefully controlled, she said. 

This is a very powerful oral medication that has a tremendous potential to help even the worst risk patients with CLL. I want to have this option available in the near future to the many of us who might benefit from it, but not at the cost of moving too fast in the clinical trials. I agree that now that we know the danger, we can take appropriate precautions. 

Personally, if  I wasn't already doing so great on my ibrutinib trial, I would not hesitate to enter an appropriate ABT-199 trial once they have the dose escalation reworked. If anything, they are going to be over cautious from here forward.

Hence my prior post on dotting the I's and crossing the T's that was my loud admonition to take it slow with drug trials.

Nice and easy does it every time.