ASH 2015: Dr. Stephan Stilgenbauer on clonal evolution in CLL (chronic lymphocytic leukemia) and update on many upcoming meetings

This week in the 2015 Conference Coverage section of the CLL Society website, we have posted an interview with Dr. Stephan Stilgenbauer as he discusses clonal evolution at the American Society of Hematology annual meeting in December 2015 in Orlando. You can see a summary and view his interview here.

Last week was very busy as I attended the CLL Research Consortium meeting from Wednesday through Friday and then took a redeye flight to Atlanta for a CLL educational meeting on Saturday. I spoke to the 30 attendees, and was thrilled that almost 90% of them already knew of the efforts we have been making with the CLL Society.

There are more meetings coming up for those of us affected by CLL:

March 12th at 7:30 AM in Scottsdale, AZ: The Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options will be hosted by the Lymphoma Research Foundation. You can find out more information and register here. There is no charge to attend.

March 17th at 6 PM in Chicago, IL: The Lymphoma Research Foundation will be hosting Updates on Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma as part of their Ask the Doctor series. You can find out more information and register here.  There is no charge to attend.

March 19th at 8 AM: The Southern California Blood Cancer Conference sponsored by the Leukemia and Lymphoma Society will be held at the Anaheim Marriott. You can find more information and register here. The CLL Society will have an exhibit table at the conference. We look forward to seeing you there. There is no charge to attend.

March 21st at 7 PM: First CLL Society Support and Education Network Patient Support and Education Meeting will be held at City of Hope: For those of you in the Los Angeles area, a new patient support and education group is forming. For more information, view the flyer. [http://www.cllsociety.org/docs/cohmarch2016.pdf] There is no charge to attend.

March 22nd at 6 PM in Atlanta, GA: The Lymphoma Research Foundation will be hosting Updates on Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma as part of their Ask the Doctor series. You can find out more information and register here. There is no charge to attend.

April 2nd at 7:30 AM: The Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options hosted by the Lymphoma Research Foundation will be held in Manhattan Beach, California. It will be held at the Manhattan Beach Marriott from 7:30 AM to 3:30 PM. You can find out more information and register here. The CLL Society will have an exhibit table at the conference. We look forward to seeing you there. There is no charge to attend.

In the meantime….

Stay strong.

We are all in this together.

Brian Koffman, MD
Volunteer Medical Director of the CLL Society

http://cllsociety.org
http://bkoffman.blogspot.com

ESH 2014: Dr. Cathy Wu Explains TUMOR HETEROGENEITY and CLONAL EVOLUTION in CLL (Chronic Lymphocytic Leukemia)

This is taken from the first of a two part interview with Dr. Cathy Wu in Greece where I spoke on the patients' perspective at a meeting of the Greek Hematology Professional Congress.

It is also a teaser of what is to come in the new website of the nonprofit The CLL Society. That CLL specific education and support site should launch in the next few weeks. It will offer much deeper and broader information and be more searchable than is possible with a blog. 

Be assured that my blog is not going away but may revert back to more of a personal blog and the place where I continue to host my candid and occasionally combative opinions and commentaries. 

Truth is that the plethora of news and emerging therapies in CLL have outgrown the capacity of my time linear blog to keep up. This new format also will offer the chances to hear other patient voices in what will be the only patient driven physician curated place on the web for CLL support and education.

I and the team of fellow volunteers are pretty excited. It's been a ton of work, but our mission is to address the unmet needs of the CLL community and we believe this new website will be a helpful piece of that effort. There is great information out there and we want to help everyone find it and explain it in our soon to be born strong and friendly CLL focused website.

Honestly, my efforts to help launch our nonprofit 510c3 and its website has consumed me, leaving less time to post here.

While we are still building phase 1 of the new website, I plan to continue to post news and interviews like this one here modified for this blog. The website will offer more links, a glossary, some surprise, and a whole lot more.

Stay tune, but I digress.

This clonal heterogeneity discussion is very important stuff on how our cancer evolves and what it means when we consider therapies.

TAKE AWAY POINTS:

·     Cancer by its nature is genomically unstable.
·     Over time it acquires more mutations.
·     New clones and sub-clones can arise over time.
·     Therapy can influence the balance and evolution of the clonal and sub-clonal populations.
·     Those changes may have significant implications for how to best manage our cancer.

PREFACE:

Hematology in general and CLL specifically are full of jargon and acronyms that can be both overwhelming and daunting.  With time and experience, you'll become familiar with the terminology and acronyms.  We will try to explain each medical term the first time it appears in an article, but we will use the true terminology so that you gain comfort and familiarity with the medical terms that you will see in your lab reports and in medical articles. We will also provide a glossary for your reference.

CLONAL HETEROGENEITY:

Dr. Cathy Wu out of Dana-Farber starts at the basics.

In the first of our two part interview from the International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment in Greece in November 2014 she reminds us that while the concept that any cancer is made of multiple populations of different cells dates back to the 70s, it is our recent ability to look deeply and quickly at the genome with next generation genetic sequencing that has really cracked open our understanding of how huge a factor this is in one’s particular CLL aggressiveness and its ability to become resistance to therapy.

We now know that questions about the presence or absence of a good or bad prognostic indicator often should not be answered with a simple yes or no.

More importantly we know that our population of our cancer cells evolves over time. Hence the need to repeat FISH and other tests when the contemplating therapy.

An analogy: In most good movies the lead protagonist has an arc to his or her character. We see how he or she changes and evolves in response to the support received or the challenges faced.

So too it is with our cancer. Unfortunately CLL is much more like a movie than a snapshot. Dr. Wu explains our cancer may evolve over time in response to therapy and other selection pressures.

Please enjoy our video interview with Dr. Cathy Wu.

If you want to dig deep, take a look at this Blood Journal abstract or this abstract from ASH 2014 or this older full text from the Journal of Clinical Oncology or this on the evolution of resistance to BTK inhibitors such as ibrutinib as just a few of the many examples of the explosion of research in this field.

Our understanding of this complicated concept is itself evolving.

I believe it is critical research with enormous implications for how we should treat our cancer. 

More to come.

ASCO 2014: Dr. Farooqui on Trials at the NIH, ABT-199, and Issues of Long Term Oral Therapies in Chronic Lymphocytic Leukemia (CLL)

In my last video interview from ASCO 2014 (several audio only interviews to come), with help from my friends at Patient Power, I interviewed Dr. Mohammed Farooqui from the NIH on the research and trials ongoing at the NIH, his enthusiasm about ABT-199 and the questions he and others are researching on longterm use of the novel oral meds.

Do keep in mind that all trials at the NIH in Bethesda are all free, with or without insurance. They even help with your airfare and hotel, and they are open to any one in or out of the USA.

The natural history trial on CLL is still actively recruiting and deserves our support. The care one will get at the NIH will be world class. A win-win situation.



It is not surprising to hear the honest response about getting adequate accrual in a chemo-immunotherapy trial is more difficult these days. I have heard similar concerns from other researchers. Now that ibrutinib and idelalisib are approved and available outside of trials, many of us are no longer considering clinical trials, especially where there is a computer randomly deciding whether we get the drug of our choice. Even trials offering an option of free ibrutinib and idelalisib are enrolling more slowly.

Dr. Farooqui also shares my excitement about ABT-199. Complete responses (CR), let alone minimal residual disease (MRD) negative responses, are rare with the two approved (though that may be changing as Dr Burger has some research showing CR and MRD negative responses with ibrutinib and mAb therapy- more on this important data point later), but CR and MRD- do occur in combination trials with ABT-199. 

I keep trying to get an answer to my question that is so pertinent for me and many others: what does it mean to walk around with residual disease (or not). There is still no answer and it will only be revealed with more time and more research. Dr. Farooqui does nicely lay out the possibilities.

Soon I will be posting some great audio only interviews from ASCO 2014 with Drs. O'Brien, Byrd, and Sharman. Next month I will be reporting from both ASH 2014 and early next week from the International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment but this is your last chance to see me with a goatee on camera.

I have not been home for more than a few days at a time in over a month. After next week, I will have been at six medical conference, in two continents, in 6 different cities, lecturing on five different topics from alternative medicine to gout to CLL. ASH in San Francisco, a short vacation in Yosemite and maybe a quick turn-around trip to London to speak on CLL are on tap before the years' end.

This crazy schedule needs to stop.

And it will.

My plan and commitment to you is that in the very near future my focus will narrow from teaching about a variety of medical topics to only focusing on my passion to spread the news about CLL and related B cell lymphomas. I have big plans and I will need your help and support to make them come true. More to follow soon.  (There is a hint of the exciting news to come in the interview).

ASCO 2014: Dr. Furman Gives us Perspective on Resistance with Ibrutinib in CLL (chronic lymphocytic leukemia)

More of My Son, Ben's Mural Work

ASCO 2014 was only a few months ago, but happily the CLL world is a fast moving place.

Since this video interview with Dr. Rick Furman of Weill Cornell, recorded and edited by Andrew Schorr and his team at Patient Power, idelasilib has been approved for CLL (see this post for discussion of its labeled indication) as predicted by Dr. Furman, and ibrutinib was approved for frontline therapy in 17p deleted patients (see this post).

YEAH to both!

Also in the intervening months, new mathematical models that consider evolution of resistant sub clones have been published by Dr. Burger out of MDACC and a high powered mathematical team headed by Dr. Natalia Komorova out of UCI. (I plan to interview Dr. Komorova as we are practically neighbors in Orange County, CA). Similar research, but this time using deep genetic analysis of the cancer's evolution over time by Dr. Cathy Wu from Dana Farber was presented at AACR 2014 Hematologic Malignancies Conference last week. (I also plan to post on her important research soon.)

The issue of ibrutinib resistance may be becoming an increasingly important issue. More and more of us are doing great with our BTK inhibited, but we still have residual disease and if you are similar to me with bad markers such as clonal diversity, 17p deletion, 11q deletion, and have a history of having been heavily pretreated (I have the first three for sure and many would say the 4th with my bone marrow transplant), then the fear of a resistant sub clone starting to act out, while still not the case for most of us even with the worst of the worst disease, is based on a growing reality of a droopy Kaplan-Meier (KM) Curve. Below are KM plots from OSU published in NATURE at the start of the year that show the downward drift in progression free and overall survival for those of us that are 17p deleted. As you can see the curves are way better than anything else out there, but they are hardly perfect.

This whole resistance issue might be largely obviated in the future by moving the new therapies up to frontline status. Dr. Furman and I both agree that is the direction we need to encourage with appropriate trials and struggles with insurers to pay for these drugs in all treatment naive patients.

Dr. Furman also mentions two exciting new BTK inhibitors, ACP-196 and ONO-4059. Click on the drugs' names to be linked to their phase 1 trials. We are just in the first chapters, but it is looking that the stories they will tell should have very happy endings. Please consider trials that offer these drugs among your treatment options.

Here is my ASCO 2014 interview with Dr. Rick Furman.



As there is a small but significant cohort of FCR patients that do great for years and years, there is a much much larger cohort of patients taking ibrutinib and other small molecules, now based on more than on more than four years of data, that should continue to do well year after year.

I am so happy for all these patients.

But I worry about the minority who won't do well, who will relapse. I am not giving up on my plea: Don't leave us stranded on 3rd base- Get us to the home plate of a cure with a follow up therapy.

We discuss obinutuzumab and ABT-199 as mop up therapies and I think those are smart choices. Maybe it will be cirmtuzumab, a new ROR1 mAB discussed in my recent post with Dr. Kipps from the very same meeting. We will only find out with clinical trials.

ASH 2013: Dr. Neil Kay on Why We Need a CLL (chronic lymphocytic leukemic) Expert and on Clonal Evolution

Dr. Neil Kay is Professor of Medicine at Mayo Clinic and also is fellow Canadian who had dedicated his career to helping those of us with CLL through research and direct patient care.

I interviewed him in New Orleans at ASH 2013.

His research has been wide and varied including the studies on EGCG (the active ingredient in green tea) that was sponsored by CLL Topics and Chaya Venkat that looked to see if there might be role for this specific extract from green tea as a gentler and more natural way to control our disease. Turns out it did have some significant efficacy, though its effect were not too powerful.

I miss what Chaya and what CLL Topics did for our community. Much of my work is an effort to pick up where she left off, but those are big shoes to fill.

In our interview form December 2013, Dr. Kay hits us with the cold facts that support my long time mantra of getting a CLL expert to head up your team. His published study has proven that we have better outcomes if we have a CLL expert on our team.

He and I discuss our shared vision of the perfect treatment team.

I can not overstate how important this is to our success in our long duet with our CLL, our nasty dancing bear of a partner. It can determine who will leads and who will follow, and how often we will get our toes stomped or worse, how often we will be forced to endure unwelcome advances by our disease.

The second topic we grappled with is more complex but worth the effort. It has to do with CLL clonal evolution.

Turns out p53 (often but not always related to a 17p deletion) is only half the story.

Turns out CLL is not a genetically stable disease. No surprise there. Especially true if you are unmutated or missing 17p.

Turns out the problem may be baked into the cancer from the start, to quote Dr. Kay it may be a "resident property of a patient who presents with CLL" and that treatment does not induce the new clones but allows what were once minor subclones to grow and become dominant. And that can spell problems for us as those clones are nearly always more aggressive and resistant to treatment.

The lessons from this research help inform us about the biology of how our cancer relapses and more importantly, about how it becomes refractory (resistant to therapy).

Dr. Kay admits that this research predates the new signal inhibitors such as ibrutinib and idelalisib and ABT-199 and more. How their use will impact the evolution of the CLL clones and subclones is a story that is not yet understood, but we can learn from this important research.

His explanation is crisp and clear. Understanding what his collaborative research has uncovered by looking at genetic evolution of CLL should help inform our decisions about when and how to treat our leukemia.

The second part of the interview will follow soon.

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.

XV iwCLL 2013: Interview with Dr. Castro on the Biology of CLL

My long time friend and crusader, Dr. Januario Castro, who works with Dr. Kipps at UCSD, besides caring for CLL and transplant patients, is doing important research into the basic biology of CLL.

He covers some of the novel bench science presented at the first morning in Cologne, Germany for iwCLL 2013.

Before you dismiss this as not being clinically relevant, I humbly suggest you that spend the ten minutes to listen to Dr. Castro making the biology easily accessed and digested. More than that, he points out some of the lingering challenges still facing CLL therapy.

Without this basic research on cancer cell biology, we could not have the amazing progress we have seen in the last few years. As Dr. Jeff Sharman said in a prior interview, the therapies explode when you crack the biology. Without the novel understandings of what is happening in CLL, we would be still be talking only about old school chemotherapy.

In this interview, first Dr. Castro is honest about what we know and don't know about clonal evolution. Next he outlines what was a recurrent theme at the conference, the important regulatory role of very small pieces of RNA called micro or mRNA. Turns out that much of our DNA is busy doing much more than just making proteins. Finally he talks about his own research that he presented on the versatility of the CLL cell, and how he hope to limit its options.



Thanks, Dr. Castro.

So much to share. I will be revisiting some of these same themes to expose some of the controversy and different takes on the same data.

 Stay tuned. A total of ten doctors interviewed over the three days.