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.

iwCLL 2013: Dr. Jan Burger Discusses More Details on How the New Targets Therapies (TKIs) work in CLL

In the second of my three part interview with Dr. Burger out of MDACC, we get into some of the gritty details about how the new novel agents such as ibrutinib or idelalisib work in the nodes, blood and marrow.

This video interview assumes you know some of the basic of how these kinase inhibitors block homing, anchoring, and communication of our malignant B cells. For a refresher, see my earlier post from iwCLL with Dr. Burger

Here in part two of that same interview, he tackles the thornier issue of the effects of the novel small molecules in terms of clearing the marrow and also discusses what we know and don't know about their ability to directly killing the cancer cells.

We are still in the very early stages of this research, and the old cliches ring true about the more we learn, the more we realize we don't know.

Some may argue that we know that they work great and that's good enough, but until we get a better handle on how they work, what are their weaknesses and strengths, we run the risk that we may not be using them in the optimal way in terms of the combinations, sequencing and duration of therapy.

This is critical stuff, and we need to fill in the details to improve long term outcomes.

We know they are very active (that is medical talk for the fact that they work) and very well tolerated.

We know that they are kinder to the marrow.

What we don't know is how and when to best use them.

We are lucky to have so many fine doctor/scientists such as Dr. Burger interested in CLL research who can translate what they are learning in their labs to help the patients in their clinics.


More soon.

iwCLL 2013: Dr. Jan Burger Discusses the Role of the Micro-environment in CLL: Part 1

On the first day of iwCLL 2013 in Koln, Germany, Dr. Jan Burger presented important basic science lab based research on how our CLL cells survive and grow in their protected niches and why it is so difficult to rid us of all the cancer calls, especially those hiding deep in our marrow and nodes.

His strong research along with the pioneering work of Dr. Tom Kipps and others helps us better understand the power of the new small molecules such as ibrutinib and idelalisib, and why we sometimes see the wild rise and slow fall of the absolute lymphocyte counts with treatment, particular with mono-therapy.

Without understanding the factors that influence the vulnerabilities and strengths of the evil clones that we are battling, we would never be enjoying the promise of the emerging targeted therapies. Instead. like the chatter for so many years at past ASH and iwCLL meetings, we would still be studying the best mix of chemo cocktails, admittedly often extremely effective, but coming packaged with all their collateral damage and long and short term risks.

We owe a great debt to all the bench scientist who are finding biological answers with potentially revolutionary clinical implications.

Here is the first of my three part interview with Dr. Burger from MD Anderson, Houston, Texas.

On a person note, today I saw Dr. Steve Forman, my transplant doctor from City of Hope for my twice a year follow-up. He agrees with the plan to taper the IVIG to every eight weeks and we have a plan to reduce my cyclosporin. More on all this later, after I get Dr. Byrd's sign off next week when I am back in Columbus.

iwCLL 2013: Day One

So far iwCLL 2013 has been a very cutting edge and bench science driven conference. Great stuff, but not easy stuff to digest.

Tomorrow that changes with more "clinical" presentations.

I need to sleep and not blog, but expect video interviews when I get home from three of the speakers today: George Calin on micro-RNA, Juan Castro on the micro-environment, and Jan Burger on a review of all the mid morning presentations.

This is important stuff we patients need to understand and the doctors that I interviewed do a great job of making it accessible. This is the basic science that molds the future of therapy that they are discussing.

Spent hours reviewing the many excellent poster presentations.

One tidbit: Notch1 and 11q del may be mutually exclusive. Who knew?

My brain is exploding. So much new information.

I will try to hold your hand as I share over the next several weeks all that I have discovered here in Cologne on day one.

Met many old friends and made some new ones. Working hard on some patient advocacy plans with some of the people here. Stay tuned.

Tomorrow looks to be just as busy or busier with at least three interviews lined up, but everything changes at the last minute.

But my son and I will make the time to get out of the conference center and see the famous cathedral before we leave. That is a must. It is only a short walk (in the rain) from our hotel.

But first I must sleep.