ASCO 2014: Dr. Sharman Reviews the Results and Implication of a Single Agent Obinituzumab Poster in CLL (chronic lymphocytic leukemia)

Another audio interview from ASCO 2014, this time with the ubiquitous Dr. Jeff Sharman, who with his work heading up a large national CLL/NHL research group, has brought us several important clinical results that has advanced our understanding of treatment options and provided directions for further research.

Here he is part of a group with Dr. Joe Flynn as the lead author, studying two different doses of the  fully humanized monoclonal type II antibody directed against CD20 (same target used by rituximab and oaftumumab) known as obinituzumab, also known as (AKA) GA101and AKA Gazyva used in this trial as single agent.

The abstract shows a strong trend to a better response with the higher dose, especially as regards complete responses. This is not surprising when we know from a dose escalation trial of rituximab published in 2001 from Dr. Susan O'Brien (mentioned in the interview by Dr. Sharman), that when it comes to antibodies, more is better.

Makes sense based on what we know about how these antibodies work. There are billions of B cells and only so much antibody. When they are all "bound up", there are none left.

There is also research now looking to see if there is similar dose response relation with CAR-T therapy: the more chimeric T-cells, the better, though the story here is much more complicated as it seems CAR-T cells are serial killers.

Dr. Kipps and I also discussed this same paper and the difference between Type 1 and Type 2 antibodies here. Dr. Jennifer Brown discusses earlier research on GA101 at ASH 2013 and the different types of antibodies here. And here are the details of its FDA approval and some of my comments only published only a little more than a year ago.

And if that's not enough background, here is an editorial from Blood 2012.

What a great year it has been for those of us touched by CLL! We are all on a fast moving train and while cure is still a distant light in the tunnel, long lasting low toxicity disease control for most of us may be a whistle stop that we blown past some time without even noticing some time last year.

Here's hoping.

Enjoy the audio interview with Dr. Sharman.


Thank you for putting up with all the pops and hisses again. I promise that they will be a thing of the past once I finish uploading the audio from ASCO 2014 and move forward to ASH 2014 and beyond.

Stay tuned as we have big plans that I will be announcing here soon that will improve our options for education and support for all of us with CLL and related B cell lymphomas in the near future.

Dosing of Ibrutinib and Other Oral Agents

"Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy."

PARACELSUS

Recently there has been some discussions among those of us who hang out at online at CLL forums such as ACOR and CLLSLL Yahoo Groups about the dosing of ibrutinib.

I am a strong believer in the power of these online communities to help us cope with our disease.

The problem inherent in peer to peer counsel is not the inaccuracy of the advice given as that also sadly too often occur in professional to patient counsel. The problem is more the lack of authority afforded any particular response. That said, if respect is earned, several regular contributors have earned my respect with their well reasoned and researched frequent comments online.

Often, especially with cutting edge therapies, the patient community is better informed about their rare disorder than the community healthcare professional who must handle the full spectrum of illness his or her chosen specialty demands.

For more on this subject see this article in BMJ  provocatively titled: What happens when patients know more than their doctors? Experiences of health interactions after diabetes patient education: a qualitative patient-led study

Case in point: Dosing of ibrutinib.

The only approved dose for ibrutinib is four tablets a day for mantle cell lymphoma (MCL), which by the way is usually a nastier disease than CLL. The Imbruvica dosing is right on the package insert.

So the community oncologist dutifully looks up what the dose to use for CLL, and finding no FDA sanctioned guidance, recommends using the MCL dose. After all,  the somewhat arbitrary dose of rituximab is the same across a wide spectrum of illness.  Arbitrary because, according to legend, the original dosing was based upon how much rituximab was available, divided by how many trial patients needed it. That worked out to be 375/M² and the rest is history.

The circumstances are less arbitrary with ibrutinib. We know that ibrutinib works by irreversibly blocking BTK through covalent binding to cysteine-481. We know that the sweet spot for getting that site fully saturated is somewhere between two and three 140 mg. capsules a day.

Moreover we know that mutation of cysteine-481binding site is an important cause of late resistance. Ibrutinib no longer fits, and the BTK pathway, and thus BCR signaling continues unabated. Not a good thing.

One sure way to increase the odds of that sinister development is to start with a low dose of ibrutinib that only partially blocks the site, but allows a significant population of lymphocytes to continue to express BTK. That is the last thing we want in cancer therapy. What we want is a SHOCK AND AWE approach to cancer. We don't want the cancer cells retreating, regrouping, and later coming back to get us by probing our weak points.

Worse yet, the up and coming second generation BTK inhibitors also seem to bind at the exact same site, so if we become resistant to oneBTK inhibitor, we may be resistant to them all. A strong incentive to get the full dosing the right from the start.

So when a doctor suggests slowly going from one to two to three or more capsules a day, it is OK for a patient to say: Can we please get a second opinion from someone with more experience with the particular drug? (Of course, there is always the possibility of the individual's extenuating circumstances that we just don't know).

Some drugs for good reasons such as allopurinol in gout needs very slow upward titration to prevent increased painful flares, but ibrutinib and most of the other TKIs should almost never be dosed that way.

Bottom line: The standard dose for CLL is three 140 mg. capsules once a day, for MCL four 140 mg. capsules once a day. Sometimes those doses can be adjusted due to adverse events or hepatic disease or concomitant medications that effect its clearance (more on that topic, specifically on the CYP3A4 pathway in another post). Short of end stage renal disease or dialysis where there is no data to go by, no dose adjustments are needed as less than 1% of the drug is excreted unchanged by the kidneys.

The right dose is more than important, it is mission critical.