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.

ASCO 2014: Dr. Kipps Discusses ROR1 and Information about a New ROR1 Monoclonal Antibody (cirmtuzumab) Trial in Relapsed and Refractory CLL (chronic lymphocytic leukemia)

Mural Detail by my son Benjamin Koffman

I am just back from a very exciting AACR (American Association for Cancer Research) Hematologic Malignancies Conference that was focused on pre-clinical research pointing the way to better therapies in the future for CLL and all blood cancers.

I will be sharing some of the most promising and clinically relevant research from that meeting in Philadelphia over the next several weeks, but first I wanted to post this timely video from ASCO earlier this year with Dr. Tom Kipps out of UCSD as there is now a chance to see how a new promising therapy using cirmtuzumab, an antibody directed at RORI will work in the real world, converting years and years of research into the first in human clinical trial.

If you haven't seen the lead up to our discussion on this brand new and very specific mAb (monoclonal antibody) targeting ROR1, then please revisit this prior post to catch the first part of our interview done in collaboration with my friend Andrew Schorr and his Patient Power team.

Remember that Dr. Kipps is a cutting edge researcher in the field of immunology and this is an immune  therapy. At the AACR meeting in Philadelphia, when I asked the father of FCR, Dr. Michael Keating out of MDACC how I might cure my own CLL, he quickly said ROR1 therapy (both MDACC and UCSD are working on CAR-T directed at ROR1- See this post with Dr. Wierda from back at ASH 2012). For many blood and cancers in general, the path to a cure means inviting an immune therapy onto the team and ROR1 is a very promising and specific target in CLL.

For more background on ROR1 by Dr. Kipps, see this, also from ASH 2012. It's a ton of long and hard bench science to bring these therapies to the bedside. Dr. Kipps has been excited about this for years and it is finally coming to fruition.

I will let Dr. Kipps tell the update of the story.



I love his push for a cure and I love his pneumonia analogy.

Now the trial for relapsed and refractory CLL patients opened recently, not too much later than the hoped for June start date mentioned at ASCO and this new ROR1 antibody, cirmtuzumab is already being used. A few patients have begun the experimental therapy, and though it is way too early to know much of value, so far so good.

Here's the link at clinical trials.gov and here is a news article on the trial.

What I like about this trial that it is an immune therapy with the promise of very little off target damage. I also like that it is so time limited- you get the 4 infusions over 8 weeks are you are done.

The downside risk. This is a Phase 1 first in human trial. Nuff said!

The dose escalation is also a potential turn off in Phase 1 trials as they are always about safety first. The hope is to find the highest dose that is not toxic called the dose limiting toxicity or DTL.

We know from our experience with the tragedies with too rapid a dose escalation with ABT-199 resulting in fatal tumor lysis syndrome (TLS) that slow and easy is the only way to go. Please see this and this and sadly this if you are not familiar with this tragic and instructive story.

The negative consequence of this emphasis on safety is the risk that those in the first few cohort may get too low or a sub-therapeutic dose.

That's why I like that this trial design. I quote from the trial site: "There is intra-patient dose escalation in the first 3 cohorts, followed by the standard 3+3 design for the next 5 cohorts."

What that means is those in the first three groups get a low dose and if they experience no problems a higher and higher dose. After that the dose is fixed for each three patient cohort.

The whole topic of Phase 1 trial design to minimize risk and maximize benefit is complicated and I am no expert, so I welcome comments from those more savvy. This is a link to a nice review article that will help if you want to dig a bit deeper.

Safety comes first and only then is drug efficacy studied more formally in later trials, but that doesn't mean there can be no measurable benefits from this kind of trial. My ibrutinib trial is sort of a phase 1 trial (1b/2) and I see no reason not to expect that this study with reveal positive results and that cirmtuzumab will eventually become an important new weapon in our arsenal to fight CLL.

For relapsed and refractory patients, admission criteria are pretty standard and there is no mention of prior transplant excluding admission to the trial.

ROR1 has been a long long time in coming.

Is it the future? It looks promising and safe in the lab and animal models, but only the clinical trials will tell us for sure.

As I have said before, the science only advances when one of patients facing a tough therapeutic decision decides that joining a clinical trial makes more sense for a host of potential reasons than standard of care. I did and it turned out to be a good bet.