How Ibrutinib and other perhaps other BTK inhibitor work over time in CLL (chronic lymphocytic leukemia)

At ASH 2016 in San Diego, CA, I had the honor of once again interviewing Dr. Wiestner from the NIH (National Institute of Health) about the prototype BTK inhibitor, ibrutinib and how and why it works so well in CLL.

We have known for a while that for its survival and well-being, our cancer is dependent on BCR (B cell receptor) signaling. Blocking BTK (Bruton’s Tyrosine Kinase), blocks that BCR signaling and that blocking usually leads to our cancer’s retreat.

This is a well-understood critical tenet of why ibrutinib works as well as it does, but it is hardly the whole story as we are learning over time.

At the NIH, Dr. Wiestner and his team not only did some of the earliest clinical research on ibrutinib, but also has been doing the bench science on exactly how it works and its impact changes over time.

Please enjoy the interview here: http://cllsociety.org/2017/02/ash-2016-wiestner-ibrutinib-cll/

Stay strong.

We are all in this together.

Brian

http://cllsociety.org

I am off to ASH 2015 to learn everything I can about CLL and I have a miserable cold.

I got my biannual cold that seems to come just as I am planning to get on the plane to the be the only family doctor among 30,000 or so hematologists and researchers from around the world.

Despite my aches and cough and runny nose, I am looking forward to learning all that I can on CLL, absorbing it and sharing it here and on the CLL Society website.

Highlights include the first data on an ew BTK inhibitor, ACP-196 (NEWS BREAK: now officially called acalabrutinib), more on other exciting drugs in development including venetoclax (ABT-199) and several promising new signal blockers and more on SYK inhibitors and new antibodies and new combos and more on approved drugs such as ibrutinib and idelalisib and obinutuzumab and ofatumumab and more smartly focused material on chemo and on new understandings of how CLL is treated in the real world and how it might be treated soon and so much more.

Plenty of interviews scheduled with experts from around the world, many whom are old friends and some who are new to me, but have published important research.

Hundreds of great abstracts (I have reviewed about 200 so far) and many oral presentations and press conferences.

I am also meeting with other patient advocates and friends from around the world to share best practices.

I will try to share some live updates from ASH 2015 because it is so exciting, but mostly I like to digest the research over a few weeks so that it can be understood and put in meaningful perspective.

The only thing missing is lots of sleep.

So now I am going to bed. Flight tomorrow AM.

The Trend is Our Friend: Living with Uncertainty with my CLL (chronic lymphocytic leukemia)

My lab test have shown a blip.

After a gradual but steady improvement in my tumor burden visit after visit at Ohio State University (OSU) during my last three years on ibrutinib (when I started it was then called PCI-32765), on my last visit my ALC (absolute lymphocyte count) rose the tiniest amount to about 2, but I didn't worry as it still was well within normal limits. It was just an unusual result for me. It hadn't been over 1.4 in a couple of years, now it was >2.

The rest of the CBC and the chemistry panel was all normal.

The next day back in California I was due for my IVIG and my repeat ALC was back down to around  1 again so I didn't think much of it. 

The fancy flow cytometry that checks for the small population of my clonal B cells, my CLL cells, is the test that really counts. That measures how many cancer cells that I still have and every test had shown fewer than the last. Both Dr. Byrd and I had predicted that already small number would continue to fall, but I would not yet be MRD negative.

What hubris!

When those results were not forthcoming in the weeks following my visit, I calmed my catastrophic flights of imaginations with reminders that when counts are too low, sometimes it hard to get an accurate result.

Then I got the news that I had a "small number of B cells" on the flow, within the expected variation seen from test to test. 

That is "doctor talk" for the fact that my count had bumped up a little, but the number was still within the expected margins of error of the test, or not significant different than the prior result. 

I still haven't seen my flow report nor do I know my absolute number. I will need to know that number at some point, but knowing it would make absolutely no difference today in what I do now, so I will try to be patient (not my best trait).

What I do know is that if the count had gone down, even just a little "within the expected margins of error" I would have been told and cheered on.

As we know that the only major group where we have seen a higher rate of relapse of their CLL on ibrutinib are previously treated patients with deletion 17p such as myself. They are the only group where < 1/2 are still progression free after less than 2 1/2 years. I have enjoyed being part of the happy minority on the Kaplan Meyer graphs.

But is this my personal start of a bad trend, the first stirrings of a tiny resistant clone that will only grow over time to become dominant? Is this the beginning of the end of my super duper run with ibrutinib?

Honestly I doubt it. 

Here's why I am honestly not worried.

A week later I received the wonderful news that my BTK and PLCG2 mutation test was negative and since nearly all CLL resistance to ibrutinib is related to a growing clone with either the BTK and PLCG2 mutation that prevents the ibrutinib from blocking signaling, odds are excellent that my lab result is nothing but a meaningless blip. Richter's Transformation (RT), the other common and more sinister cause of relapse on ibrutinib, tends to occur early in treatment and three years out is not early.  I don't have RT. No signs or symptoms.

So although I won't rest completely easy until I see my next flow cytometry results sometime after my next OSU clinic visit in August, odds are really with me on this one.

The trend is our friend, and as I have coached so many others, I now must heed my own advice: One lab test means nothing.

I will be traveling for a couple of weeks in Poland on a Jewish Heritage trip with my rabbi. One purpose of the trip is to forget all about CLL and our nonprofit CLL Society for a few days, but I will be busy in the evenings in Eastern Europe writing for the CLL Society website (some great stuff from the CLL Research Consortium or CRC Patient Empowerment and Education Meeting and from EHA coming soon) and more critically, for a peer reviewed medical journal on CLL due the beginning of August. 

I am alright with that crazy balancing act though I do worry what I will eat in Poland, not exactly a vegan's paradise.

Last chance for the CLL (chronic lymphocytic leukemia) Survey and the News About the Agreement between Gilead and Ono

We are taking down the survey at midnight tonight Pacific Time, so if you haven't completed it, please let us know what will be important to you in a CLL website and support groups.

Here is the link to the survey: https://cllsociety.questionpro.com

And thanks so much to the over 400 of you that completed the survey and the many who have made a donation to the CLL Society Inc. to jumpstart our process.

                                  


Finally I want to share this press release from Gilead:

ONO  AND  GILEAD  ANNOUNCE  EXCLUSIVE  LICENSE  AGREEMENT  TO  DEVELOP  BTK  INHIBITOR,  ONO-4059,  FOR  THE  TREATMENT  OF

B-CELL  MALIGNANCIES  AND  OTHER  DISEASES

-- Companies will Collaborate Jointly on Global Development of ONO-4059 --

Osaka, Japan, and Foster City, CA, December 18, 2014 - ONO PHARMACEUTICAL CO., LTD. (“ONO”) and Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the companies have entered into an exclusive license agreement for the development and commercialization of ONO-4059, ONO’s oral Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of B-cell malignancies and other diseases.  Under the terms of the agreement, Gilead will pay ONO an upfront payment plus additional payments based upon achievement of certain development, regulatory and commercial milestones.  The companies will collaborate jointly on global development of ONO-4059.  Gilead will have exclusive rights to develop and commercialize ONO-4059 in all countries of the world outside of Japan, South Korea, Taiwan, China and the Association of Southeast Asian Nations (ASEAN) countries, where ONO retains development and commercialization rights.  

ONO-4059 is a selective, once-daily, oral inhibitor of BTK, which has been shown to play a role in the survival and proliferation of malignant B-cells.  ONO has presented preliminary Phase 1 data showing clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) at several scientific conferences.  ONO and Gilead plan to develop ONO-4059 for the treatment of B-cell malignancies and other diseases as a monotherapy and in combination with approved and investigational agents, including combinations with kinase inhibitors in Gilead’s portfolio. 

“We are pleased to partner with Gilead to accelerate worldwide development and commercialization of ONO-4059,” said Gyo Sagara, ONO’s President, Representative Director and Chief Executive Officer.  “Our goal is to bring better therapeutic options as quickly as possible for the patients with B-cell malignancies or other diseases in the world, and we believe we can fulfill the goal by pursuing the development of ONO-4059 with Gilead.”

“With this agreement, Gilead now has compounds targeting four unique signaling pathways associated with B-cell malignancies – PI3K delta, Syk, JAK and BTK,” said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer.  “In addition to evaluating ONO-4059 in combination with standards of care, we believe there is an opportunity to combine this compound with Gilead’s other kinase inhibitors with a goal of achieving more pronounced and more durable response rates.  We look forward to working with ONO to move the ONO-4059 development program forward as quickly as possible.”

About ONO PHARMACEUTICAL

ONO PHARMACEUTICAL, headquartered in Osaka, Japan, is an R&D-oriented pharmaceutical company committed to creating innovative medicines in specific areas. It focuses especially on the diabetes and oncology areas.  For more information, please visit the company’s website at http://www.ono.co.jp/eng/index.html.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need.  The company’s mission is to advance the care of patients suffering from life-threatening diseases.  Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Gilead Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including risks that the parties will be unable to develop and commercialize ONO-4059, as a potential monotherapy and in combination with other therapies, for the treatment of B-cell malignancies or other diseases.  These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements.  The reader is cautioned not to rely on these forward-looking statements.  These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014, as filed with the U.S. Securities and Exchange Commission.  All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

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This is good news as we need more options and Gilead is a smart company that has a strong track record on getting new and important drugs approved. It also has other small molecules including idelalisib that might make sense in combination therapies. The market seems to approve of the move as this joint effort should increase the likelihood we will be seeing ONO-4059 become commercially available.

Ibrutinib is a great BTK inhibitor and has set the bar very very high in terms of its response rates and tolerability, but still it won't be the right choice for all patients due to some intolerance or adverse outcomes or lack of efficacy, so having another Bruton Tyrosine Kinase inhibitor option is something all patients should want.

And waiting in the sidelines is Acerta's ACP-196- no data to report yet, but the buzz about this new BTK inhibitor is very promising.

Abbvie, Janssen, Pharmacyclics and others are looking at new non-chemo combos in trials in the hope of going from control to cure. More on these trials and plans soon.

2014 was a great year for those with CLL. 2015 may be even better.

Happy Holidays to all.