Friday, August 10, 2018

ASH 2017: Dr. Adrian Wiestner on Resistance Mechanism in CLL (chronic lymphocytic leukemia)

I had the opportunity to interview Dr. Adrian Wiestner from the National Institutes of Health at ASH 2017 in Atlanta GA about his and other researchers work on how CLL cells become resistant to ibrutinib and venetoclax.

Take Away Points:
  • Ibrutinib works so well in chronic lymphocytic leukemia because it blocks the B-cell receptors (BCR) by binding to Bruton’s Tyrosine Kinase (BTK). This blocking of the BCR leads to cell death.
  • About 7-8 out of 10 patients who become resistant to ibrutinib develop a mutation C481 that prevents it from it binding and thus fully blocking BCR, allowing the CLL to progress.
  • PCLƔ2 mutation is another cause of resistance as it turns back on the BCR pathway and gives a lifeline back to the chronic lymphocytic leukemia cells.
  • Cells with the PCLƔ2 mutation tends to grow more slowly and the CLL tends to clinically progress more slowly.
  • Notch1 mutation can be associated with early progression on ibrutinib which is often not CLL but instead Richter’s Transformation that carries a poor prognosis.
  • Many patients do well on ibrutinib who have a Notch1 mutation.
  • Richter’s is rare after the first year on ibrutinib suggesting that blocking B-cell signaling may block the stimulation that leads to Richter’s
  • Less is known about the mechanism of venetoclax resistance, but upregulation of MCL-1 might play a role.
Conclusion:

While the numbers are small, we are starting to better understand the mechanisms of resistance for some but not nearly all patients who progress on ibrutinib. Our understanding of venetoclax resistance is much less mature. As this research develops, there is reason to be optimistic that we can develop drugs to overcome the resistance.

Here is my interview with Dr. Wiestner from ASH 2017 in snowy Atlanta Georgia:



Here are links to some of the research referenced by Dr. Wiestner


Here is more on resistance from Dr. Furman from our website.

Thanks for reading.

Stay strong

We are all in this together.

Brian Koffman

Sunday, August 5, 2018

He Did It

Hi,

Stan Kurtz and his team, with help from so many of you, Did it. He swam the Catalina channel and raised his goal of over $25.000 for the CLL Society! Thanks to all who gave, but it's not too late to share in there joy. Consider a tax deductible (in the USA) got of $22, one dollar for each mile he swam in over 12 hours in the Pacific Ocean. Or more. It was an exhilarating and exhausting for Patty and me just being on the boat.

Now I need to get some sleep. 

Thanks 

SEE: https://www.gofundme.com/swimcatalinaforleukemia. The swim was on the local TV news. This will help us to do so much more for others dealing with CLL.

Lot's of pictures and videos on our and his FB page,

Stay strong.

We are all in this together.

Brian

http://cllsociety.org

Monday, July 2, 2018

10 years ago today I received my Transplant for my CLL (chronic lymphocytic leukemia)

July 1, 2008, Canada Day, was my first Day Zero- my first shot at a cure when after conditioning chemo-immunotherapy of FCR, I received my hematopoietic stem cells from an unrelated donor who I later discovered was from Israel.

The allogeneic HSCT didn't work- though the chemo gave me a short but deep remission. I never engrafted, and when I quickly relapse, my cancer was meaner, a 17p deletion had shown up and my chronic lymphocytic leukemia required a new approach.

The transplant did however buy me some time before I needed treatment again and the longer you wait, the better are the new options that are bee developed.

Fortunately my timing was great. When I couldn't put off therapy any longer, I was able to jump onto and ride a trial of ibrutinib, then called PCI-32765 in a phase 1B trial out of Ohio State University for seven great years and form many new friendships, especially that with Dr. John Byrd, my doctor at OSU.

When I could no longer ignore the fact that the ibrutinib had stopped working, that my CLL had mutated around it, I swung for the fences again, this time with a most experimental CAR T trial at the Seattle Cancer Care Alliance.

My second Day Zero was March 22, 2018 when I infused with my own generically modified T cells.

After a very, very rough course, documented in my CAR T blog, I am MRD (minimal residual disease) negative- I have no detectable CLL in my blood, my nodes or my marrow.

September will be 13 years since I was told that I had cancer. I should have been dead years ago, but I took risks that paid off, and as of today, I have the least leukemia on my body that I have ever had since diagnosis.

The extra time has allowed me to blog and establish the nonprofit CLL Society that is making a difference for thousands of CLL patients around the world.

I am one lucky guy and my future looks bright.

Monday, May 21, 2018

I've go to admit it's getting better: More good news about my CLL (chronic lymphocytic leukemia)

Most of my blog posts can be followed here.

The full story of my CAR-T therapy, the incredible rollercoaster and the amazing results can be found there 

I have been too slow to post good news, but let me share that my deep sequencing testing done on my bone marrow biopsy at day +28 post CAR-T showed no copies of the CLL DNA. I discuss what this means in more detail in my blog posts here: https://cllsociety.org/car-t-blog/  My celebrations are detailed in the previous post.

Also on the CLL Society website proper is an interview with Dr. Dearden about combos in CLL ( they are the future for high risk patients) and other topics plus tomorrow we are posting Dr. Brown on bleeding concerns with ibrutinib. The news is reassuring.

Slowly getting back into the swing of things. Went to the San Francisco CLL Society support group yesterday and talked on the phone with the NYC group where Dr. Furman made a guest appearance to help answer questions.

Feeling stronger myself.

Stay strong.

We are all in this together.

Brian

Wednesday, March 21, 2018

GET MY CAR-T CELLS TOMORROW FOR MY CLL

Patty and I have been enjoying Seattle. We’ve been here for 3 weeks prepping for the JCAR14 trial at SCCA/Hutch. Tomorrow is my big day- I get the CAR-T cells.
I’ve been blogging on my experience on the CLL Society website http://cllsociety.org and we are adding interviews and research on CAR-T (see: https://cllsociety.org/car-t-and-other-cellular-therapies/) but that may slow down if I am part of the 90% that end up in hospital. Check out our CAR-T educational comic book while you are there on our site.
Anyway, I wanted to stay in touch and look forward to continuing the conversations when I am on the far side of this with no evidence of CLL left in my blood, marrow, and nodes.
Stay strong. We are all in this together
Brian
Brian Koffman MDCM DCFP, DABFM, MS Ed
Founder and Medical Director, CLL Society Inc.
http://cllsociety.org
PO Box 1390
Claremont, CA
91711

Sunday, March 18, 2018

Goldilocks and the CAR-T cells

I had planned to write more often, but long hospital days, followed by long naps and long walks most days have precluded me doing much more than remembering my trial schedule and completing a hurricane of critical paperwork and lengthy CLL Society’s to-do lists while I am still able to work.

Despite my sincere intention to be here and now in a more public way, blogging has taken a second seat to more mundane needs. And to my own health priorities like sleep and exercise.

But I have clinical studies to share now.

Two days ago, I got my results, and the news was mixed.

My blood chemistries were all good except for a slightly elevated LDH consistent with a cancer on the move.

My blood count showed a continuing slow downward trend in my HGB (today it was 11.9) and a slightly climbing lymphocyte count in the high teens now. Platelets and neutrophils remain within the normal range.

Just a few months ago my lymphocyte count was 1 and HBG was 14. My CLL is taking off.

Bone marrow biopsy (BMB) was hypercellular at 65% suggesting it has had to expand due to infiltration with leukemic cells. In fact it showed that more than 80% was filed with lymphocytes, leaving less than 20% of the factory floor to make all my red cells, platelets and other white cells.

By flow cytometry about half of the white cells were clonal, consistent with CLL.

The one surprise was that no 17p or 11q deletion was detected Hard to explain. May be a sampling or technical error, or that a different CLL sub-clone without those deletions has become predominant in my marrow.

My last BMB five years ago had normal bone marrow cellularity at 40% and only 20% was lymphocytes. That was on ibrutinib while it was working well.

My CT scans last week were filled with” innumerable” enlarged lymph nodes, but at least they were all less than 4 centimeters in their longest diameters.

My PET scan showed those nodes to be metabolic active, but the highest SUV was only 4 making Richter’s Transformation (RT) less likely. However, PET scans may be less helpful in predicting RT in those failing novel therapies.

For comparison, two and half years ago, I had no enlarged nodes with imaging.

 Clearly my CLL is on the march in the blood, marrow and nodes and it is time to treat.

So here is where Goldilocks comes into play.

If one’s CLL “tumor burden” is too high, especially if one has “massive” lymph nodes greater than 5 cm. and certainly greater than 10 cm. there is suggestion that the army of CAR-T cells may have too many enemy combatants to wipe out or they may be too far out of reach, even for these hyped-up serial killers.

If one’s tumor burden is too low, there is a chance that the genetically reengineered cells won’t get enough stimulation to expand and will just die off without ever engaging in battle.

So there is a sweet spot, Goldilocks’ just right bowl, where the T-cells are stimulated to expand but are not overwhelmed by the amount and depth of the cancer. The way T cells kill is up close and personal. They need to wrap their arms around their targets, and if they can’t get right up against each and every CLL cells in a massive node, the cancer will live on.

In fact, published CAR-T responses tend to better in the blood and marrow than in the nodes.

My odds of a deep and durable response are excellent based oy my labs and imaging.

However, the risk of cytokine release syndrome (CRS) and neurotoxicity may also be correlated with the total amount of disease burden (not so much the size of any one node, but the sum of the diameters of all the nodes), and by that criteria, I have more than enough disease to suggest I will have a wild roller coaster ride ahead of me.

While this is an evolving science and all of the data are immature, especially in CLL, the way I read the tea leaves is that I am predicting a great final outcome but am buckled up for the fight of my life ahead of my restaging one month post CAR-T infusion

Looks like I will need to get worst to get better.

Wish it weren’t so but it is what it is. I say bring it on.

Stay strong.

We are all in this together.


Brian

Tuesday, March 6, 2018

3/6/2018 Brian's Apheresis at SCCA for CAR-Ts to treat CLL

Patty reporting from Seattle Cancer Care Alliance March 6, 2018: Apheresis! Using a sophisticated centrifuge, Brian’s T-cells are being spun off and will be genetically re-engineered to form the CAR-Ts. Brian’s arms are busy at the moment, but this little inconvenience is outweighed by great optimism. To see this procedure from the T-cells’ perspective, check out our CAR-T Comic Book here:  
https://cllsociety.org/2018/…/simple-fun-introduction-car-t/ More later. Patty