Initiation and Discontinuation of Ibrutinib in Chromic Lymphocytic Leukemia (CLL)

It is not often one gets this much brain power and experience with ibrutinib around one table so I am very grateful to OncLive for arranging this discussion and wanted to share it here.

I was surprised by Dr. Byrd's hesitancy about using ibrutinib frontline.

I was not surprised by the lack of unaminity among the experts.

Here are some of the key points.

1. The immunological modulation effects of ibrutinib are emphasized by Dr. Byrd. It is doing more than interfering with B cell signaling. Same may be true for idelalisib.
2. The future is combination therapies, but what do we do now? Ibrutinib is approved as monotherapy. (That is why we need more trials.)
3. Dr. Furman points out that some Imbruvica patients are continuing to improve 4 or 5 years down the line, getting to CR and even MRD negative.
4. Dr. Kipps doesn't buy we ever get MRD negative if one uses the most sensitive tests, especially in the bone marrow.
5. No-one really knows when to stop therapy.

There is much more between the lines here. Give a listen.



It seems there are three potential visions of how things may play out.

Below, I have grossly oversimplified the three doctors' nuanced perspectives to highlight the wide spectrum of opinions about what may come to pass with the new CLL agents.

• Dr. Furman talks about a significant subset of patients that tolerate ibrutinib therapy well and continue to improve over long period of time, and so we argues why rock the boat and stop therapy, at least outside a clinical trial.

• Dr. Kipps and I agree that you can't get to CURE without passing by MRD negative first, and he wants to be able to stop therapy because the cancer has been once and for all eradicated.

• Dr. Byrd offers a slightly different possible outcome. Treat to get to MRD negative (likely with a combo), stop therapy, and then a very very long durable remission, maybe never requiring more treatment.

I am sure the difference are matters of emphasis and there is much agreement. And much uncertainty.

As Neils Bohr, the Nobel prize winning quantum physicist said: Prediction is very difficult, especially about the future.

Blood Cancer Conference in Anaheim on Feb. 7, 2015

We are getting excited about our CLL Society's very first presence at a patient event, especially because it will be at the LLS Blood Cancer Conference on Feb. 7 in Anaheim. Will you be there too? Drop by our table and say hello. I helped arranged to have Dr. Kipps give the CLL speech and Dr. Rosen the keynote so it should be a great meeting as are all the LLS activities.

Register here.

No more deaths from CLL (chronic lymphocytic leukemia)?

Will there soon be a day that there will be no more deaths from CLL (chronic lymphocytic leukemia)?

That may not be possible.

The better question is whether we soon can give everyone one of us with CLL a very very long and high quality life with the diagnosis.

With support and education and research, that is absolutely possible.

Online and local support groups, educational blogs (like mine and others) and CLL focused websites help inform the best possible decisions.

Today, a significant number of us CLL patients, if we choose wisely and get a lucky break or two, can have a very long run with little price to pay. And that number is growing.

But still too many of us get lost on the road or get banged up on the trip  or worse, blindsided by a fatal accident despite reading all the road signs and making the best possible decisions.

I, like everyone in the CLL forums, am dedicated to educating and supporting my fellow CLLers, but that is only one step. We need more and better treatment options. We also need to reach more fellow patients and providers alike about the best options already available, with therapy decisions being made based on the best evidence and the preference voiced by us patients.

Our work is daunting, but I believe we are getting close.

That is what drives the efforts of this blog, the nonprofit CLL Society Inc., and many many others.

Stay strong

We are all in this together.

This was Not Supposed to Happen

Dr. Aaron Caplan's widow, Michelle says it best, but it a story with the saddest of endings.

This is not a post for the faint of heart, nor is it meant to be a downer for us survivors with CLL. '

Maybe its only utility is to remind us to live every day to its fullest, to ask us to accept that we really have much  less control than we imagine, and to urge us to push hard to find smarter and gentler therapies.

Here are Michelle's unedited words, shared with her permission.

This wasn't supposed to happen.  

Aaron had planned to come home to New York today or tomorrow to prepare himself for further treatment.  His doctors had begun applications to three centers for a very promising t-cell therapy that would either precede or take the place of a second bone marrow transplant using his sister, Elana, as the donor.

Aaron was not suffering.  He had not given up.  He told our children the night before he passed that they were the reason that he was getting better.  He told me that he would never leave them when they were three and five years old.  He planned to enhance their lives for years to come.  He told me that I looked tired and that he was excited to rest up together as soon as he was home.  On Monday I believed that we would survive and thrive once again.  That our family was safe.  

It is true that we found ourselves in a difficult situation last month with the news about the secondary lymphoma but Aaron always believed that we would make it through this crisis and that, in the end, it might lead us to the elusive cure.  He wondered if he hadn't endured enough before that last transplant and that perhaps he would need to be brought to the brink of death in order to rise again.  No matter what it would take, we planned to do it together and come out the other side into another beautiful stretch of years.  

He began chemotherapy on Tuesday December 16th, the very same day that the Richter's transformation was confirmed with the results of a lymph node biopsy.  That night he drove home from Boston, organized his work, rose at 3:30 am (his usual time--the day was never long enough for him) and worked straight through until Friday.  Saturday he played with our children, cuddled with me, and made dinner for his family.  He was tired but not sick.  The photo that has been shown of the four of us was taken on Saturday December 20th, the day before he went into the hospital.  He was very much alive and focused and excited to see our children perform in their winter solstice concert.  This was not a man who was contemplating death.

The hospitalization was sudden and complicated by this strange and intense hip pain that forced him onto pain killers that made him psychotic.  Aaron was always a lightweight.  He never even took an Advil so to have his system overrun with morphine and Atavan was overwhelming.  Though that day-to-day challenge sparked many concerns for brain bleeds, infections and strokes, he was simply under the influence of the medication.  And what we feared might be metastatic disease to the hip was a musculo-skeletal injury that was worsened by the injection administered to stimulate his bone marrow.  Aaron's cell lines had been blown out by the chemo and his system needed time to recover.  Aaron had patience.  He was willing to endure the many discomforts that accompany low counts.  He never complained.  But we knew that he needed better care.  

Once we relocated him to Boston, the pain was quickly brought under control and while he was exhausted from the ordeal, Aaron was once again oriented and ready to move forward.  His team had begun a new chemotherapeutic regimen that was quickly shrinking his enlarged lymph nodes. We hoped to see a rebound in his counts this week as the cancer levels in his bone marrow were brought under better control.  Aaron was walking around the transplant unit on Monday with a PT, doing squats, and lamenting that what had been a body in the best shape of his life was suddenly so deconditioned.  He intended to turn that around.  Aaron had wanted me to bring the kids home so that they could get back to their routine.  I was not supportive of this decision but he was always the one to put the children ahead of himself.  He was happy to hear their squeals of delight as they raced about and reconnected with their space.  I was counting down the days until we could bring him back into our house that did not quite feel like a home without his presence.

Tuesday morning, I called him on the way to school and learned that he was having trouble breathing.  He said that they thought he had pneumonia.  To be honest, I became a bit hysterical as I did not want to see one more thing stand in our way.  Aaron reassured me that all was well, that it was a slight thing, offered the kids his love, and then the line went dead.

I could not get him back on the phone.  We never spoke again.  I soon learned that Aaron did not have pneumonia but had suffered a bleed in his lungs that was making it hard for him to breathe.  The doctors believed it was from one blood vessel that needed to be repaired.  I agreed to the procedure, packed the car, retrieved the kids and headed to Boston.  Thankfully not alone.  Sasha and Mira's teacher and my friend, Lorna, could see my distress and offered to drive us.  Throughout the drive, we received updates.  Most of them led me to believe that Aaron had a good chance of survival.  

When I arrived, his mother, Louise, was told that Aaron had survived the procedure and that we could see him in a few minutes.  At that time, I imagined his release would be delayed.  Nothing more.  I was completely unprepared for the hastily delivered news that he had spontaneously begun to bleed again, that he had coded twice, and was essentially about to die.  

Aaron and I never said goodbye.  Aaron never wrote letters to the children.  Death was not part of our plan.  And in no scenario that I could have ever envisioned was Aaron lying on a table covered in his own blood while I begged him, and God, and every one of the thirty doctors and nurses who surrounded us to save this most amazing man.  My love.  A father who devoted himself to his children.  A doctor with an amazing brain and work ethic.   I couldn't have seen myself nearly on top of him, holding his face, and tasting his blood as his incredible spirit moved out of his body.  I couldn't have believed I would hear from a doctor that the reason for this situation was disastrously bad luck.  But that is what happened.

And it should not have happened.  

Aaron should be on his way home to us.  We should be walking forward arm in arm.  This is what we wanted.  This is what we fought for.  This is what we clung to every day as we loved each other and our children and this incredible life that we had built together.  We fought for life until the end.  He deserved the best kind of luck at every turn.  

Aaron Caplan was kind, generous, loving, brilliant, joyful, energetic, always smiling, embracing life and those around him every minute of every day.  We never fought.  No one ever fought with Aaron.  He operated on an entirely different plane than most people.  He should have had the chance to go on.  I don't know how to do so without him.  He was our whole world.  

Michelle also wrote me:

Aaron so admired you and wanted to donate to your site. I would like to direct people as to how to do this.  Can you please tell me?

If you want to support our nonprofit 501c3 CLL Society Inc. effort to meet the unmet needs of the CLL community, there is Donate button on the very top of this page.

If you prefer to mail a donation, please send the check to:

CLL Society Inc.
PO Box 10546
Newport Beach, CA
92658

Thank you.

May Aaron's memory be a blessing.

There is One Less Doctor/Patient with CLL (chronic lymphocytic leukemia) Alive Today

More bad news.

After a 10 year struggle, a young friend (in his mid 40s) with very young children, a fellow MD with CLL, just passed away from complications of his leukemia.

Being a doctor, even a very thoughtful Harvard trained doctor, and being treated at world class medical centers, and making all the smart decisions, and getting randomized to the "right" arm of the trial, and getting the best possible therapies and living a clean lifestyle, and being a hardworking, good person, and having the love of your family and friends and the respect of your colleagues and the prayers of many, none of it provided a free pass.

This is the second doctor/patient that I personally have known that succumb to this disease.

When it comes to CLL there is no immunity. Double entendre definitely intended.

I hate this cancer.

Mostly I am just so sad for his wife and his children and the rest of his family.

And angry (but I am not sure at what- the cancer I guess).

My prayers goes out to his loved ones.

I am also so motivated to do what can be done to increase all our odds of avoiding a premature death. It's possible. It's close. But we are not there yet.

I and several other CLL survivors from our Orange County CLL support group will be at the LLS Blood Conference Feb 7 in Anaheim.

Please click here to learn more.

On behalf of LLS, I extended an invitation to Dr. Tom Kipps of UCSD and Dr. Steve Rosen of City of Hope and was thrilled that they both accepted to speak. It will be super meeting, so don't miss it.

Please register and when you are there, please drop by our table for the CLL Society Inc. the new nonprofit 501c dedicated to the unmet needs of the CLL community. Learn how with your help, we plan to make a real measurable difference in the years to come and do what we can so that everyone has the best possible odds.

ESH 2014: Prof. Stephan Stilgenbauer Discusses Prognostic Factors, FCR and Implications for Therapy in CLL (chronic lymphocytic leukemia)

In part two of my interview from ESH in November 2014 from Greece with Professor Stilgenbauer of the University of Ulm, Germany we go deeper on the topics we cover in part one and introduce new subjects. I recommend you take a look at that post if you haven't already. That prior post also has links to even earlier reviews of some of the same areas of discussion.

In this segment, the doctor starts by using the examples of 11q or 17p deletion that help explains some of the subtleties of the difference between prognostic and predictive factors.

It is a nuanced subject, but one worthy of our efforts to understand as it can help guide our therapeutic choices.  His examples clearly outline the differences. Hopefully my brief introductory notes that follow also help.

The best known bad player found by FISH or interphase fluorescence in situ hybridization is deletion of 17p.

When the short arm of the 17th chromosome (17p) is deleted, gone with it is TP53 that is important in maintaining genomic stability when our DNA is reproducing itself. Because of its critical role in guarding the fidelity of each copy of the genome when our cells are replicating, it is considered a tumor suppressor. The doctor explains how it also fosters resistance to most chemo-immunotherapies.

The number two bad boy is 11q deletion.

The 11q arm carries ATM that is also involved, those less critically, in the same pathway protecting the stability of our genome. But the new discovery is that 11q deletion may also lead to loss of BIRC3 that leads to the jamming on of the pro-survival and anti-apoptotic NF-κB signaling pathway. More on this in later posts.

It's complicated, but the pieces are coming together.

Dr. Stilgenbauer points out that in those of us with 17p deletion with the relatively good news of having a positive mutation status, our CLL may be slow to progress. This combination of + mutation status and 17p deletion is an example of a prognostic factor- prognosticating about how we will do in the future.

He next points out that when patients with that same combo eventually do need treatment, it will most likely not respond to conventional chemo-immunotherapy (CIT) such as FCR. This is an example of a predictive factor, representing a "prediction" of the likelihood of a given therapy working.

If we are both unmutated and 17p deleted, sadly odds are we will both progress quickly and do poorly with traditional therapies. A double whammy. Bad prognostic and predictive factors. That's me.

He correctly points out the good initial response rates to CIT for those with 11q deletion (I am in this group too), but he neglects to point out that while we might get a deep response, it is not durable, possibly due to our cancer's ability to mutate more freely. He is right in highlighting the strong correlation between unmutated status and 11q deletion, which raises the questions about which is these two gives us the bad prognostic.

The professor's take on the possible "cures" with FCR is also instructive. Please give a critical listen.Much to ponder.

We also talk about the need for deep sequencing to search for 17p deletion or to check for TP53 function. He explains the new versus old ways to look at the chromosome.

Dr. Stilgenbauer outlines the sinister consequences that happens when the selective pressure of CIT is applied to even the smallest subclone population of 17p deletion cells. They can rise up and take charge when the cancer returns.

I believe that FISH is important but only a first step. Today we need to look for both deletions missed by FISH and smaller but critical subclones that are beyond the resolution of FISH. CLL management needs to move in this direction.

I don't want this post to be too much of a downer. While all statistics and cellular biology are important for predicting what happens to different groups, they do not determine individual destiny. And many of the new therapies' responses are blissfully blind to FISH status. I myself am unmutated, 11q deleted, 17p deleted, ZAP 70+, CD38+, have a complex karyotype and I am doing fine, thank you, but knowing this helped informed my decisions.

He closes with the familiar clarion call of the twin needs of having a CLL expert on our team and for more research.



More from ESH, Greece coming soon, including Dr. Wu on clonal heterogeneity and Dr. David Porter of U. Penn on CAR-T in CLL.

Many interviews to share from ASH last month in San Francisco are on the way.

Stay strong. We are all in this together.

Personal Comments on Comments

Just a quick reminder again that I often get comments on my posts that ask for a response, but I never receive your contact information, so if you want to contact me and me to contact you, please email at bkoffmanMD@gmail.com and I will try to respond.

I of course can not give medical advice by email or though a blog post, but I hope I can share some helpful information.

Remember too that as recent hacks have shown, email may not always be that private, so please carefully consider what you write.

Stay strong.

We are all in this together.

Brian

Why Patients Need to Be Heard At Medical Congresses: The Patient's Perspective on CLL (chronic lymphocytic leukemia)

Here is the hope that this season of miracles offered up its miracles to those of us in need.

And if the time is not right for miracles, then let's at least do what we can to be sure that the researchers and doctors acknowledge and take into account our concerns about what we want from our providers, our therapies and our clinical trials.

If I can't get the miraculous cure, I want some incremental movement towards better therapies for all us.

This is the second part of a 5 part series on my take on the very specific topic on what the patients' voices should be part of medical congresses.

And that is just the start.

Our voices must be heard at the meetings between researchers and funders on how trials are set-up, at IRB (institutional review boards) that approve those trial designs and any subsequent revisions, payors who decide what treatments get covered and what don't, and of course in our doctors' offices when we are planning our therapy using a shared decision making model.

Listen to the first brief section monologue published on Dec 4, 2014 where I introduce myself

Here is the next segment.



Please let me know what you think?

More soon.