Frontline Therapy for CLL (chronic lymphocytic leukemia), And on Stress and Living Long

This week in The Basics section of the CLL Society's website, we’ve posted an article that I wrote about Frontline Therapy that what factors are considered when making treatment decisions for frontline therapy. You can view that article tomorrow here. http://cllsociety.org/2016/09/frontline-therapy-cll/

The next issue of The CLL Tribune will be available on Wednesday. It’s hard to believe it’s been a year since our first issue. Stay tuned for a special email alert!

A CLL Doctor List is posted in our CLL Toolbox. This list is composed of CLL physicians recommended by our readers. Thanks to those who have provided updates and additions since we posted it. We’ll be incorporating them soon! You can access it here. http://cllsociety.org/toolbox/cll-doctors/

It is not a vetted list, but a list from the readers.

I am in Ohio now for my every 12 week rendez-vous with Dr. Byrd and the team from OSU to check on the status of my tiny resistant clone. 

I am anticipating more good news- that things are all stable, but it is always a bit nerve wracking waiting for my lab results. My palpable nodes remain small, but I am tired.

I have been under terrible stress related to my work as a family doctor. That paid work, which I love and hope to continue for many years if at all possible, supports all my activities as the unpaid volunteer medical director of the CLL Society. 

I am wholly unconvinced that stress makes CLL worse. If it did, mine would have exploded by now.

From here, I fly to Tampa to meet with Dr. Javier Pinilla-Ibarz out of Moffitt to look at ways we can work together to help CLL patients and set up a support group.

Here's a little cool travel news- completely unrelated to CLL.

Guess who was standing next me in the custom lines when we returned to LAX from Lisbon? 

I was not more than 5 feet away from Mic Jagger who looked thin and fit and very healthy.  As I said, maybe stress and a frantic lifestyle is good for you.

ASH 2015: Dr. John M Pagel on Idelalisib as Frontline Therapy in CLL (chronic lymphocytic leukemia)

We have just learned of the good news of the broad FDA approval in the USA of ibrutinib in the frontline setting for CLL.  

This step forward in CLL therapy only comes after years of research and is due in no small part to the brave patients who volunteered for these trials including the pivotal RESONATE-2 trial.

As a reminder, ibrutinib is a small molecule taken orally, a tyrosine kinase inhibitor or TKI, that inhibits the BTK pathway that is so important for  B cell communication. By doing so, it blocks a critical pro-survival signal in our CLL cells and helps control our disease. 

I will comment more on the significance of this frontline approval in a coming post, but to give some perspective, I want to reflect on the only other approved oral TKI for CLL, namely idelalisib that inhibits the PI3Kδ pathway. This pathway is also important for B-cell signaling in our CLL cells and blocking it also blocks the same strong survival signal. That is a big part of the reason why both these drugs work as well as they do. 

Researchers want to discover which CLL patient will get the most benefits with the least risks from these new therapies.

At ASH 2015 in December, many researcher were initially surprised by the amount of toxicity discovered when idelalisib was studied frontline or in the treatment-naive CLL population. 

Keep in mind that it is currently only approved for use in combination with rituximab in the relapsed and refractory CLL population, not frontline. This trial was to look at its safety and efficacy in this new setting.

I interviewed Dr. John Pagel of Swedish Hospital in Seattle, WA on the importance of this negative findings.  

It is a truism in science that we often learn as much or more from the trials that don't go as planned as from those that do.

Though most of the research on idelalisib presented at the ASH meeting was positive, the title of this abstract tells us there were significant issues:  Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities.

Three quarters of the patients had grade 3 toxicities or severe problems. For 56% of them this was liver toxicities where the blood tests that measure liver inflammation were 5 to 10 times the upper limit of normal. These are much higher levels than generally seen when idelalisib is used in patients who have had prior treatments.

The good news is that with immune suppressive therapies including steroids, all the patients recovered.

The details of the trial are here.

Why then when ibrutinib is relatively benign in the frontline setting, did a somewhat similar drug have such unexpected problems.

Any drug may have effects on cells that are not their therapeutic target, resulting in unwanted side effects. One theory is that idelalisib lowered the balancing activity of the regulatory T cells or Tregs that are important in preventing auto-immunity. The PI3Kδ pathway is critical to the function not just of CLL cells but of the Tregs too. 

This is why we need to do research. This is why we need to laud the brave subjects who jump into these trials. Without them, we make no progress.

Here is my interview with Dr. Pagel on this subject from ASH 2015.



As Dr. Pagel emphasizes, idelasilib is a powerful drug that helps many patients with CLL. How and when to best use it is a matter of ongoing research.

Stay strong

Brian

Forbes says: "With So Many Terrific New Drugs For Chronic Lymphocytic Leukemia (CLL), Why Worry?" I say it's a Tempest in A Teapot

Hydra (mythical monster that grows two heads when you cut off one)

Elaine Schattner wrote a provocative and helpful editorial in Forbes: With So Many Terrific New Drugs for Chronic Lymphocytic Leukemia, Why worry? I recommend we all read it, but that we also read it critically.

It has to do with her concerns about the dangers of unnecessary treatment.

My friend and fellow cancer advocate Andrew Schorr wisely reminds of us a friend with CLL who has done very well without treatment for nearly 18 years.

We know that about three out of every ten of us diagnosed will follow a very indolent (slow) course and never need treatment.

And so the author cautions us to avoid unneeded therapy. Good counsel. Never take a treatment that's not needed. All drugs and I mean all drugs have side effects. 

Her concern and motive for her editorial is that thousands of us will rise up demanding that our hematologists offer us the new expensive therapies just because they are so darn safe and effective when we would be better off doing nothing, just watching and waiting. Hordes of CLL patients will ignore the carefully tuned 2008 iwCLL guidelines on treatment, and demand an immediate prescription NOW before we are in troubled waters.

I believe it's a false concern. 

A powerful and practical reason that Ms. Schattner is worrying over nothing is that these expensive drug are not yet approved frontline  with the notable exception of ibrutinib in 17p deleted patients as detailed in this recent post). It is highly unlikely our medical insurance is going to pay for an off label use of a pricey therapy when there is ZERO data to support it. And of course, there are vanishingly few of us that could afford the out of pocket cost of at least several thousand dollars per month for any of the new star therapies (in order of appearance on the CLL stage): ofatumumab, obinutuzumab, ibrutinib and idelalisib. And of course, even frontline approval is not the same as approval (and insurance coverage) when there is no indication to treat.

That said, I am sure that there will be a few patients among us who will think it is the height of craziness to sit on our hands. We should strike the cancer while is still in its infancy well before it has the time to achieve its typical mature persistence and wily ways, making it such a formidable foe, making a cure still a dream for almost all of us. Kill it before it grows into a multi headed hydra.  

But a quick review of the facts should dissuade us from this tempting but false path. There is absolutely no evidence that early intervention helps. In this oft quoted article from 1988, Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation, and this one from the NEJM in the same year show we learned that there was no survival advantage to early intervention. And there are certainly risks. Studies such as these reinforces the importance of knowing the data and also knowing where there is no data.

Wait you say: Chlorambucil may have been state of the art in 1988, but today we have better therapies. Might not the results be different if we looked again using today's drugs? 

Good question. The same sort of trial was set up with FCR, but died on the vine due to lack of enrollment.

That is why trial such as this closed trial on using lenalidomide or this new one using ofatumumab are so important and need our support.

Although prognostic factors such as FISH and ZAP 70 and mutation status tell us much about a group of individuals and little about the individual members of that group, wouldn't we all want to jump out of the high risk frying pan and get far far away from the heat in the kitchen to a calm and cool place of low risk if we could do so by intervening early?

That's is exactly why we need more studies to answer if it is possible to save more lives by using the new mAbs such as ofatumumab and obinutuzumab and the new TKIs such as ibrutinib and idelalisib and others in the pipeline before we traditionally need treatment. There is good reason to believe it just might be so, but without data…. it's only conjecture.

So what do I recommend?

I believe all these drugs should be moved towards more frontline therapy for all patients with the help of well designed trials,  not just those of us with high risk prognostic factors.

I believe these drugs should be studied in those of us with high risk unstable disease BEFORE we need treatment. 

And maybe I am about to sound like a doctor when I say this: I also believe that outside of a clinical trial, there is absolutely no role for these drugs for patients who don't meet criteria for treatment.

The Forbes editorial ends with some sage advice:

“As with other malignancies, the best way to prevent overtreatment is to assure that doctors are current in their education, knowledgeable of “lesser” treatment approaches, and not motivated by financial incentives to give therapy. And for patients, the best prophylaxis is to know that not all conditions carrying a malignant label warrant treatment. Patients might ask, “What’s the least toxic therapy you can give, so that I’m likely to stay alive with the quality of life I want, with this particular form of cancer?”

That's precisely what we are trying to do here. Educate doctors and patients about low toxicity options.

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