Saturday, January 16, 2016

Relapse After Four Years on Ibrutinib

Dave’s Great Adventure
Book 5, Chapter 2, Verse 12
January 12, 2016

Well, we had a great run, didn’t we, ibrutinib and I? I’ve been using the stuff for almost four full years and it has done wondrous things for me. I was pretty sick, with an aggressive mutation of my CLL. I had a white count of almost 100,000 and large, swollen lymph nodes throughout my body, including masses up to about 8 inches in diameter in my belly, chest, neck and under my arms. Life expectancy without treatment was said to be about 16 months or so at that point. Wow.

When I started on the Phase1/2a study of ibrutinib, in April 2012, the researchers had just completed a study on the first 110 patients and needed 40 more for the next step. I was extremely lucky to have been given one of those 40 openings. I was added on to the second phase of the study which added the anti-leukemia-cell antibody, Rituxan. I’d had this drug before with most of my other treatments, but never before in such close-together doses, as I was treated with the stuff weekly for the first five weeks of my therapy before backing off to four more monthly doses. It and the ibrutinib worked spectacularly well. I honestly could tell it was working within the first week. I could feel the pressure being taken off my belly as the tumors rapidly began shrinking. I was amazed and thrilled!

Within months my white counts normalized, my bone marrow biopsies were close to normal and my CT scans showed the tumors melting away. I was in clinical remission. And everything stayed stable with normal white cell counts from that point on. My low platelet count didn’t come back to normal, like I’d hoped, but just about everything else did. I began feeling fairly normal again. And just as I had during past remissions, I started forgetting I had the disease. It didn’t seem to really be a part of my life anymore, so well was it suppressed. Kathy and I have felt that way before, as if it no longer existed.

But we know better. CLL is an insidious disease. It almost always comes back, and every time it comes back, it tends to be more aggressive. The remissions tend to get shorter and shorter. But in between these relapses you start to feel pretty good and can almost forget you have the disease, so normal does life seem. And then just when you’re thinking you’ve beaten the disease…it’s back.

Now, even though I was in clinical remission for many months, even years, and felt much better, I have to confess that I didn’t feel completely normal. I had the joint pains that many folks taking this wonderful drug have complained about, but it was never debilitating and the pains were just intermittent. Yeah, I sometimes had to limp around for a day or two, on a sore foot or knee, and sometimes it hurt to move my wrist into certain positions, but the problem almost always took care of itself with a few days. I know lots of folks who had to take lots of drugs like Motrin or Naprosyn and such because of their pains. But that creates other problems, since the ibrutinib makes your platelets less able to clot. The Motrin-like drugs make that issue worse and can increase bleeding problems.

More seriously, I’d been having occasional heart rate irregularities, specifically one known as atrial fibrillation, usually shortened to “a.fib.” A.fib is known as an “irregularly irregular” heartbeat, wherein the heart beats with no regular rhythm at all. That’s unlike the irregular heartbeats many of us feel from time to time, when we have a few extra heart beats before our heart resumes its regular rhythm (after too much caffeine, too much stress or too little sleep). A.fib is a problem because when the heart has no regular rhythm, clots can form in the upper chamber of the heart and then travel to various parts of the body. When clots travel to the brain, they can cause a stroke. A.fib has been found to be increased in folks who are taking ibrutinib.

I got through my first couple of years on the drug before having my first episode of a.fib, but have had a half dozen episodes since then. The usual treatment for a.fib is what’s called a cardioversion, or shocking the heart back into a regular rhythm. That’s what you see on all the hospital shows where they put the paddles on someone’s chest and yell out, “Clear!” before shocking the patient. I’ve been scheduled for cardioversions in the Emergency Clinic twice, but fortunately my heart has resumed its regular rhythm on its own each time, within about eight hours, before I got to the ER early the next morning. I’m currently on a heart medication known as flecainide which helps control abnormal rhythms. We’ll see if it controls the a.fib well enough. I also take an anticoagulant medication named Xarelto when I notice that I’m in a.fib to prevent blood clots from forming.

And I’ve been tired. A lot. Many folks with CLL complain of fatigue and there seems to be more of that when on ibrutinib. But, I have denied, I think, how significantly tired I get. I don’t like to admit to weakness, so I get along the best I can and keep doing what I need to do, but there are days when I am very, very tired. There have been times I have told Kathy that I was “desperately” tired. On those days, I was having trouble keeping my head up and my eyes open. There have been days when we’ve had to cancel our activities so I can just rest. Yeah, I’ve been tired and it seems to have gotten worse in recent months. I was blaming the increased fatigue on a case of bronchitis that I’ve been fighting for months, but relapsing disease will do that too.

I’ve known for a couple of years that researchers had found that the enzyme which the ibrutinib attaches to (the BTK enzyme, Bruton’s tyrosine kinase) which helps it kill off CLL cells, can mutate so that the drug can no longer attach to it. That makes it less effective. I just didn’t know how long that might take to happen and how often it happens. In fact, I don’t even know for sure if that’s what happening to me. To tell the truth, I can’t even be sure that I’m in a relapse with certainty until a bunch of recent tests which are in progress are completed, but I know, with certainty, that my white count, which had been about 5,000 for a couple of years, went to 6,000, then 12,000, then 14,000 and now to 35,000. And 70% of the 35,000 white cells are lymphocytes and all CLL cells are lymphocytes! I had been thinking that the increased white blood cell counts were because of the bronchitis I was fighting and the steroids I’d been taking, but the steroids shouldn’t increase the lymphocyte percentage, just the bacteria-fighting neutrophil white blood cells. And that’s not good news. But it had to happen someday, I suppose.

But even if I’m truly relapsing, I have to tell you that I’ve been so pleased to have been on this wondrous drug for the past four years. At a minimum, it kept me from needing a transplant, a risky procedure which I surely would have had to endure by now if not for the excellent results of the ibrutinib treatments. And my side effects have been minimal. I have had little to complain about, and much to be thankful for.

So, now what? Well, as I have said to many of the folks who have contacted me about having CLL, we now live in something of a “Golden Age” of CLL research and treatments. When I initially got sick, way back in 2002, there was really nothing that was very good we could use to provide durable remissions. But, just then, Dr. Keating and his crew at M. D. Anderson came out with the FCR regimen, a combination of Fludara, Cytoxan and Rituxan. They achieved remarkable results with this combination therapy. In fact, some folks treated back then have STILL not relapsed and are cautiously being said to have been cured over 10-15 years since their treatments.

And now we have, not only ibrutinib, but several similar acting drugs called idelalisib, ABT-199, and now a second-generation ibrutinib-like drug named ACP-196, which is currently in trials. It’s said to be as effective as ibrutinib but with fewer side effects. And there are others in trials too. Plus, the “immune checkpoint inhibitor” drugs are now being developed. These drugs release the body’s own immune system to attack cancers of various types. These, too, have been developed at M. D. Anderson. You may have heard that former president Jimmy Carter has an aggressive skin cancer called melanoma which has spread to his brain. He is, I believe, being treated with an M. D. Anderson-developed drug called Yervoy. The last report I heard was that the tumors in the president’s brain had disappeared. That’s amazing, as melanomas are almost always rapidly lethal.

Similar drugs have been developed against lung cancers and other solid tumors. And now the researchers are ready to start treating CLL with these drugs as well. I believe that is what Dr. Keating has in mind for me, though we’ll need to talk about my various options and each option’s risk/benefit ratios.


Let me spend just a bit of time talking about the immune checkpoint inhibitors (hopefully without causing your eyes to glaze over!). I need to start by discussing our white cells. Everyone knows that our white cells protect us from infections and such. But, our white cells are made up of many different types of white blood cells, each with different functions. We have bacteria fighting neutrophils, antibody-making B lymphocytes (which can become CLL cells!), tumor suppressing T lymphocytes and several others, including NK (“natural killer”) cells, basophils, eosinophils, monocytes and more. For now, just pay attention to the T lymphocytes. These guys constantly patrol, our bodies looking for abnormal cells which may be becoming cancers or other tumors. They do this by looking for unusual proteins on the surface of these abnormal cells. But many cancers can fool the T cells by masking these abnormal proteins. They cover up, if you will, with proteins that the T cells think are normal. When this happens, the T cell leaves the abnormal cancerous cells alone and so they can spread.

But, if an immune checkpoint inhibitor is given, it prevents the cancerous cell from fooling the T cells, so the T cells can release chemicals to destroy the tumor. There’s no chemotherapy involved in this. The immune checkpoint inhibitors are just special antibodies created to block the cancer’s ability to fool the T cells. The body’s own normal T cells are then allowed to do what they’re supposed to do and they kill the tumor just as they would any other abnormal cell they come across. Pretty cool stuff!


Now, this has not been tested in leukemias, to my knowledge, but studies are underway. I may be able to be a Guinea pig yet again, just as I have for so many studies and experimental protocols over my “career” with this disease. Hey, this could be exciting.

Now, I know I may be getting a bit ahead of myself, since I don’t know with absolute certainty that I am actually relapsing, but it sure looks that way. In fact, just as I was writing this chapter, I looked up some of my new labs on the M. D. Anderson web site, and I see that my test called a beta-2-microglobulin is going up. That’s almost certainly a sign of disease progression. I’ll find out the details on our return trip to Houston in three more weeks but that’s what I’m expecting.

I am so very grateful for the world class care I’m getting in Houston. I have all the confidence in the world that they’ll do what is absolutely the best treatment for me and it will be tailored to my specific disease type as much as possible. I literally trust Dr. Keating and his crew with my life. But I also know that at some point, eventually, this disease is likely to take me down. As I said before, what CLL does is that it can come back time and time again until it becomes untreatable, even in the very best of hands. A couple of years ago a personal friend of Dr. Keating’s, who was also a co-founder of Dr. Keating’s research foundation CLL Global, died of complications of CLL after having dealt with it for over 20 years! I heard that Dr. Keating was extremely depressed after this event, as you’d expect. But the disease is going to do what it’s going to do even when being fought by the very best methods and scientists in the world.

Anyway, that’s where we are for now. Hey, this blog was getting too boring anyway!


“It is an inescapable part of the human condition that we live our lives on the knife edge of the present, forever trapped between an unchangeable past and an unknowable future.” –John Steele Gordon