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.

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 Abstract: ABT-199 in Relapsed and Refractory CLL Patients

I have posted before on ABT-199. I like this drug because it works. And it is a pill, not an IV.

It is clearly a very potent therapy.

We know that not just from the impressive 85% response rates, even for those difficult to treat 17p del and F refractory patients where an amazing 88% and 75% respectively achieved at least a partial response (PR), but we also know it from its dark's side, namely tumor lysis syndrome (TLS).

Until the dosing was adjusted after the first cohort, the first three patients all had TLS, a life threatening complication (and one die did in this trial) from the massive killing of the cancer overloading the liver and especially the kidneys' ability to prevent all that toxic waste from cell death from building up to dangerous levels.

We need to move carefully, but I am glad that ABT-199 is back in trial after the studies were suspended due to deaths from TLS.

The present approved options for F-refractory and 17p deleted patients are severely limited and these results are very promising.

Complete responses (CR) are only 13%, but that's not bad for any mono therapy, especially in these tough patients.

Our future depends on the researchers taming both the disease and the drugs that we use to treat it.

We also need to constantly recognize the sacrifice of those who bravely jumped into this "first-in-human" phase 1 trials. CLL is not for wimps.

The question I am asking myself is will ABT-199 offer enough of a therapeutic potency edge over the other novel oral therapies such as the gentler inhibitors of BTK and PI3K∂ that will justify its risks and earn a place in our therapeutic arsenal.

Or will its risks become acceptably manageable? Whatever that means.

Still is nice to have more viable choice options for those of us with bad disease.

I hope it move forward. I imagine a time that we will take a cocktail of oral pathway blockers to completely slay our dragon, much as is done today with HIV. Blocking BCL-2 is part of that vision.

Here is the abstract.

Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
John Francis Seymour, Matthew Steven Davids, John M. Pagel, Brad S. Kahl, William G. Wierda, Thomas P. Miller, John F. Gerecitano, Thomas J. Kipps, Mary Ann Anderson, David C.S. Huang, David E. Darden, Lori A. Gressick, Cathy E. Nolan, Jianning Yang, Todd A. Busman, Alison M. Graham, Elisa Cerri, Sari H. Enschede, Rod A. Humerickhouse, Andrew Warwick Roberts; Peter MacCallum Cancer Center, Melbourne, Australia; Dana-Farber Cancer Institute, Boston, MA; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Wisconsin Carbone Cancer Center, Madison, WI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Arizona Cancer Center, Tucson, AZ; Memorial Sloan-Kettering Cancer Center, New York, NY; UC San Diego Moores Cancer Center, La Jolla, CA; Royal Melbourne Hospital; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; AbbVie, Inc, North Chicago, IL; Royal Melbourne Hospital, Melbourne, Australia
Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with >500-fold higher affinity for BCL-2 (Ki< 0.10 nM) than for BCL-XL (Ki = 48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (>15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in > 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose- escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626. 

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ABT-199 is Coming Back

ABT-199 is soon coming back to trial near you and this could be very good news.

News release from AbbVie (formerly part of Abbott):

ABT-199, our next-generation BcL-2 inhibitor in development in partnership with Roche/Genentech, was featured in a special symposium at the American Association for Cancer Research (AACR) annual meeting earlier this month. AbbVie recently proposed an amended study protocol for ABT-199 in chronic lymphocytic leukemia. Upon approval by the U.S. Food and Drug Administration (FDA), dose escalation and new patient recruitment will resume.

Much tighter monitoring, immediate sharing of adverse data between sites, and slower dose escalation  done in an inpatient setting, are my guesses as to what will be part of the restart. 

As I have discussed before over a few posts, the best way to kill a good drug is to rush it to market. 

A patient told me this trial may reopen as soon as June. Here's hoping.

ABT-199 offers very powerful disease reduction, but at the risk of potentially fatal tumor lysis syndrome or TLS where the cancer is killed so effectively and so fast that the kidneys and other organs can't cope with the toxic waste produced. This has been seen in flavoperidol (where there is required pre-emptive care), lenalidomide, and other CLL drugs. It can usually be handled with careful monitoring and appropriate aggressive medical intervention including dialysis for the worse patients, and should be preventable for the majority with cautious dose escalation and meticulous monitoring.

Blocking BcL-2 as discussed in my prior posts with Dr. Tom Kipps, is an attractive target in CLL and a logical piece of a intriguing future non-chemo cocktail in combination with something such as idelalisib or ibrutinib that might offer outstanding durable disease control.

I am glad ABT-199 is coming back.

Finally, our celebration of this possible important new arrow in our CLL quiver with forever be tinged with sadness over the loss of the two brave volunteers who died in the trial from TLS. I won't diminish their sacrifice by saying that it allowed this progress. No, instead I simply suggest that we need to insist on trials that are well designed to maximize benefit and minimize risk. Truth is most are, but we are dealing with so many unknowns. Adverse events and even deaths are never fully preventable, and it is too easy be critical in hindsight. After all we are talking about experimental therapies (see post by Dr. Furman on Phase I trials) but we need to constantly remind the researchers that bring us these new options to always put safety ahead of expediency. That may be no fun us lab rats either, perhaps slowing the time it takes until we get to the dose where we respond and maybe even demanding that we are admitted to hospital overnight, but such is the cost of progress.

In trials using multiple sites, bad news must travel fast to ensure necessary adjustments are systemic and near instantaneous.

Even with all these precautions, there will always be risks, so I forever laud the brave subjects who without whom there would be no progress. 

My readers know me to be strongly pro clinical trials. For many of us, the risk of the trial is less than the risk of traditional therapy or doing nothing. I still feel that way, and still encourage everyone to consider  an appropriate clinical trial.

All I am saying is let us do what we can to minimize all our risks.

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.