Wednesday, November 20, 2013

The Ibrutinib Failure Rate

Dave’s Great Adventure
Book 5, Chapter 2, Verse 5
November 21, 2013

I have just returned from yet another trip to Houston to visit with Doctor Keating and his staff to see how I was doing. I expected the results to be fine as I have been getting blood tests monthly here in Denton, in between my visits to Houston, and those tests have been pretty close to absolutely normal, the only minor issue being that my platelets, the cells that help your blood clot, are still a bit low at about 100,000 (with 150,000 or higher being the normal number). But, 100,000 is still high enough for my blood to clot normally and is not a worry at all. And, indeed, everything they checked in Houston is also pretty close to normal, both with my lab exams and my physical checkup.

I have been taking ibrutinib, this near-miraculous new drug, for about 20 months now, and it continues to work very well for me and, seemingly, just about everyone else who has entered a clinical trial using it. My side effects continue to be pretty minimal. Many of the early symptoms I was having during the first few months on the combination of ibrutinib and rituximab seem to have mostly resolved. I still have occasional flares of redness and tenderness along the ligaments and tendons in my feet, hands, ankles and wrists, but the pains are never debilitating and rarely require any treatment with anything more than Motrin or Aleve.

And every time I go to Houston I ask how the other folks in the study are doing and I have routinely been told that everyone seems to be doing fine. There are still 40 people in the study I’m in, and the manufacturer has just opened up another 80 slots for more patients. In addition, most of the 90 or so people who were in the Phase I study at MDA are still taking the drug as well. And I know there are other folks in similar studies in Washington, DC and, I believe, at Vanderbilt, as well. But I really don’t have a good feel for how many patients there are, total, taking this drug right now. Probably less than a few hundred. I keep hearing that everyone expects the drug to be approved for general use by the end of the year. I hope that comes to pass as I still hear of folks dying of this miserable disease and I know they would have been saved if they’d been able to get into a study with this stunningly effective drug.

And not only is this wonder drug working well on CLL, but they have now found that it shows promise in other malignancies like mantle cell lymphomas, Waldenstroms macroglobulinemia and I believe it’s being tried in patients with multiple myeloma as well, but I’m not as certain about those studies yet.

More information about these studies will be made public soon, as the annual meeting of the American Society of Hematology will be held in New Orleans next month, and their findings are always made available on-line in their magazine, Blood, very soon thereafter. I look forward to seeing what is reported.

But, there is a cloud on the horizon. Just in the last few weeks I have learned that they are finding some failures of ibrutinib in CLL patients, after about 30 to 48 months on the drug.

The drug is incredibly effective in bringing just about all of us with the disease into a clinical remission very rapidly, and it does so regardless of our CLL sub-type. If you’ve been reading my stuff very long, or have been researching CLL on your own, you know that in the last decade our wonderful researchers have found that there are a number of sub-types of the disease, depending on your chromosomes that appear in your diseased CLL cells. These chromosomes may have loss of part of the chromosomes, as in the 11q deletion or 17p deletion (in which a part of the 11 or 17 chromosomes have lost a part of that particular chromosome), or they may have an extra 12 chromosome as in the “Trisomy 12” sub-type. And, there are a few others as well. Some of these mutations make the disease more aggressive; some make it less aggressive. Most patients with CLL tend, with time, to mutate toward the more aggressive types, it would seem. The above mentioned 11q and 17p deletion sub-types are the most aggressive of the mutations.

Well, regardless of how aggressive your disease is, based on your cell mutation type, ibrutinib clears the diseased cells rapidly. It does not kill the CLL cells directly but rather just “allows” them to die a natural death in a timely manner by releasing them from the lymph nodes and bone marrow (where they tend to hide under the protection of “nurse-like” cells) into the circulation where they die off. These diseased CLL cells are still being made in your body, but they are not allowed to accumulate and cause the patient any problems. So ibrutinib is not a cure.

But now we are seeing that there are drug failures at some point in certain CLL sub-types. As I mentioned, after about 30 to 48 months on the drug, they are finding some failures but thus far, they seem to be only in the 17p deletion patients. This is the most aggressive of the types of CLL because the missing part of the 17 chromosome is a very important gene known as the p53 gene. This is the gene that tells cells to die if they have been damaged.

Chemotherapy generally works by damaging the DNA of the cells it attacks. When the DNA has been damaged, the p53 gene will instruct the cell to die. However, if that specific gene is absent, as in the 17p deletion patients, the damaged cell will keep growing. This is why chemotherapy is almost futile in this specific type of patient. This is “my” type of CLL.

Having heard that failures have been found in recent months, I asked Dr. Keating what percent of the 17p deletion patients were showing signs of this problem. He simply replied that it’s “common.” I suppose the number of patients affected is still small, as the total number of patients taking the drug is still fairly small, but it’s a troubling finding for the folks like me who are afflicted with this aggressive mutation.

And, what will we do if/when we fail? Well, we still have options. One possible option that I’ve heard mentioned is to switch us to yet another type of the tyrosine kinase inhibitors, similar to ibrutinib, which are being tried against CLL. A year or two ago I wrote about the several drugs of this type which were being developed. I called them the “license plate drugs,” as they all had names (at the time) like PCI 32765, CAL 101, AVL 292, ABT 199 and so on. These anti-CLL drugs are all still in Phase I or Phase II studies, but they’re out there. I have to believe that switching us to another tyrosine kinase inhibitor would involve setting up yet another clinical trial, because I don’t believe I’ve heard of this being done anywhere yet.

The next option would to be to get into a CARs clinical trial. In my last “verse” I wrote about the chimeric antigen receptors (CARs) studies, in which a patient’s own T-lymphocyte white cells are collected from the bloodstream, treated with a retrovirus to inject DNA into them, which “teaches” them, if you will, to attack CLL cells. Then the treated T-lymphocytes are put back into the patient to kill off the CLL cells, wherever they are in the body. This, in theory, should be able to effect a “cure” of our disease. A very few patients in Philadelphia (three patients, actually) have been treated for CLL in this manner and though they have had some complications, two of them seem to be free of disease. A CARs study is in the making at MDA and they will very soon be recruiting patients into the trial. CARs have also been used with some success in a few other types of leukemias, but in very limited numbers so far.

And the last option would to be to undergo a stem cell transplant. After having gone through a stem cell transplant evaluation in early 2012, just before I got into the ibrutinib study, I have been seeing the transplant folks at MDA on a regular basis, every 3-6 months, just to keep in touch as they will be my last hope if all else fails. Stem cell transplants can be life-saving but they can be fraught with risks. To start with, there is up to a 25% risk of dying of the transplant procedure itself. And if you are among the 75% who survive, there is the very real possibility of long-term graft versus host reactions, where the transplanted cells attack your body, because they don’t recognize you as being normal. But, when a transplant is your last hope, you go for it and I will too when the time comes.

And so, that’s my ibrutinib update.


Mike died a few months ago. I mentioned Mike in my stories about a year ago, when I told you how lucky he and I were. At the time Mike had Stage 4 lung cancer which is, by definition, terminal. His lung cancer also had the 17p deletion, just as my CLL does, which made it that much harder to treat. When I met Mike I’d recently found that I had developed the 17p deletion CLL, the most aggressive type and I had just failed a course of a new drug called Arzerra. But we were both Vietnam vets who were able to come home to our families and we had great lives for decades after Vietnam, unlike many of our buddies. And even though we were both fighting incurable diseases, we were enjoying our lives and had just wonderful support from our families and friends. He and I were guinea pigs for various clinical trials of new drugs and procedures but we were glad to be in those studies. We commiserated a lot about our fates but knew we were lucky to have lived as long as we had. Mike told me his dad always said, “Everybody wants to live forever but nobody gets to.” Mike fought the good fight until the side effects of his many experimental and standard treatments became too much to bear. And then he made the incredibly brave decision to forego more therapy and eventually checked into a hospice. There he died peacefully, in the same room where his mother, too, had passed away in the hospice.

Key died a few months ago. Key was the head nurse for my local oncologist here in Denton. I’d known Key for years and she was the type of person who would drop everything to help you when you had a problem. She had a constant smile on her face and had hugs for everyone. She checked into the hospital for a routine surgery, which was successful. Then she came home, started feeling poorly and went back to the hospital, where she died suddenly. She was in her 50s and left behind a daughter in college. Everyone who knew her misses her.

Kristen died in June. My second cousin, Kristen died of pulmonary fibrosis, a particularly cruel disease which affects the lungs, making the membranes thicker and thicker and slowly unable to absorb oxygen until you get to the point where you simply suffocate, even as you are gasping for air. Her father, brother and her only uncle also died in this manner.

One of Dr. Keating’s long time assistants died recently. She had worked with him for many decades. In a particularly ironic turn, she died of an incurable lymphoma. To be working at a place like M. D. Anderson and then develop and die of a lymphoma is just somehow unthinkable, yet it happened.

And since I developed my own incurable disease and started whining about my mortality, I have seen many, many wonderful folks who were a part of my life die. My high school buddy, Kent, died of complications of diabetes, as did our daughter-in-law’s dad, Nat, and my young colleague Abby, who developed diabetes in her early 20s and died within a few years. And my friend Jim Brettell, who died of a blood clot after a simple, “uncomplicated” knee surgery. And my mom and her husband, my step-dad, who both died of heart disease. And both of my wife’s parents. And our neighbor, Beverly, who died of Alzheimer’s. And my dermatologist’s head nurse. And the list goes on. All around us people are dying in car wrecks and of disease. The newspapers report the stories every day. Death is commonplace.

My point is to say that I have come to recognize that my death, whenever it occurs, will not be a big deal. Yeah, it seems like it should be a big deal, because I’ve never died before, but it’s a passage we all will make at some point. Being born is a “terminal” event and always ends in death. We all, intellectually, know we’re going to die at some point, but emotionally we don’t believe it. Our experience seems to show that we “won’t” die. People around us die but we never do. So it’s hard to accept that fact. Even if we’re in great health, and strive to remain that way, we’re going to die. As I’ve quoted someone in the past, “Good health is merely the slowest possible way to die.”

I have a serious disease which had killed millions of people before me, including my own father. But I have great care, care that hasn’t been available to me or anyone else until very recently. However, this wonderful new care, with all the new drugs and possible transplant procedures, is not going to keep me alive forever. As an oncologist (cancer doctor) told me many years ago, “It’s your oncologist’s job to keep you alive long enough for you to die of something else.”

And when my time is drawing nigh, I hope I’m able to be as brave as Mike was and not start whining again.

I’ll be going back to Houston for another evaluation next February and will probably get an update out shortly thereafter.


Buddhist Parable of the Mustard Seeds

Kisa Gotami had an only son, and he died. In her grief she carried the dead child to all her neighbors, asking them for medicine, and the people said: "She has lost her senses. The boy is dead.” At length Kisa Gotami met a man who replied to her request: "I cannot give thee medicine for thy child, but I know a physician who can." The girl said: "Pray tell me, sir; who is it?" And the man replied: "Go to Sakyamuni, the Buddha."

Kisa Gotami repaired to the Buddha and cried: "Lord and Master, give me the medicine that will cure my boy." The Buddha answered: "I want a handful of mustard-seed." And when the girl in her joy promised to procure it, the Buddha added: "The mustard-seed must be taken from a house where no one has lost a child, husband, parent, or friend." Poor Kisa Gotami now went from house to house, and the people pitied her and said: "Here is mustard-seed; take it!" But when she asked “Did a son or daughter, a father or mother, die in your family?" they answered her: "Alas the living are few, but the dead are many. Do not remind us of our deepest grief." And there was no house but some beloved one had died in it.

Kisa Gotami became weary and hopeless, and sat down at the wayside, watching the lights of the city, as they flickered up and were extinguished again. At last the darkness of the night reigned everywhere. And she considered the fate of men, that their lives flicker up and are extinguished. And she thought to herself: "How selfish am I in my grief! Death is common to all; yet in this valley of desolation there is a path that leads him to immortality who has surrendered all selfishness."

Putting away the selfishness of her affection for her child, Kisa Gotami had the dead body buried in the forest. Returning to the Buddha, she took refuge in him and found comfort in the Dharma, which is a balm that will soothe all the pains of our troubled hearts.

The Buddha said: "The life of mortals in this world is troubled and brief and combined with pain. For there is not any means by which those that have been born can avoid dying; after reaching old age there is death; of such a nature are living beings. As ripe fruits are early in danger of falling, so mortals when born are always in danger of death. As all earthen vessels made by the potter end in being broken, so is the life of mortals. Both young and adult, both those who are fools and those who are wise, all fall into the power of death; all are subject to death.

"Of those who, overcome by death, depart from life, a father cannot save his son, nor kinsmen their relations. Mark I while relatives are looking on and lamenting deeply, one by one mortals are carried off, like an ox that is led to the slaughter. So the world is afflicted with death and decay, therefore the wise do not grieve, knowing the terms of the world. In whatever manner people think a thing will come to pass, it is often different when it happens, and great is the disappointment; see, such are the terms of the world.”

Friday, June 7, 2013

Remission, Ibrutinib...and SciFi CARs

Dave’s Great Adventure

Book 5, Chapter 2, Verse 4

It’s been way too long since I last wrote in this journal and long-running story. When I go long periods of time without writing, it has always meant that things are going quite well, as it seems to me that there’s nothing worth writing about. But folks who read this journal but don’t have any other contact with me often don’t know whether I’ve just stopped writing, have died or maybe have left the on-line community. For this I apologize. I should let folks know when things are going well just as often as I do when they aren’t going well. But for the last many months, everything has been going extremely well.

I am now in clinical remission. Note the “clinical” qualifier. Most folks with cancer look forward to the day they are in remission, as for most diseases, like breast cancer, bowel cancer, prostate cancer and so on, that word equates to an eradication of their disease. But I am in “clinical” remission, and happy to be so. With my particular disease, that does not mean my disease has been defeated and is gone.

When I go to M. D. Anderson for my checkups, my blood tests and my physical exams are normal. So, “clinically” I appear normal and in remission. However, if one does a flow cytometry test on my blood or bone marrow, closely examining the cells in my blood, we find that there are still substantial numbers of leukemia cells in my body.

In fact, the aggressive form of leukemia which I have is still growing just fine within my bone marrow and lymph nodes, but this new wonder drug, the PCI 32765 (ibrutinib) is, essentially, whacking the abnormal cells as fast as they form by keeping them from hiding out in the nodes and marrow. When they’re out in the bloodstream, unprotected by the “microenvironment” of the lymph nodes, they die on schedule, like they’re supposed to. So, they don’t have the opportunity to harm me. Because, the way the cells of CLL harm you is by accumulating in large numbers in the bone marrow and lymph nodes, forcing out the normal blood cells we depend on for life; our red cells, our bacteria fighting white cells and our clot producing platelets. Now, with this new drug, they don’t have that opportunity. My lymph nodes are shrinking and my marrow is clearing its accumulated CLL cells.

I was declared to be in “clinical remission” last November, after about eight months of taking the ibrutinib, and after completing a six month course of Rituxan, the antibody which also attacks leukemia cells. Since that time I have had periodic blood tests, physical exams, another chest and abdomen CT scan and bone marrow biopsy. All is looking good. No…actually, all is looking great!

All of my blood test numbers for red cells, white cells, platelets and neutrophils either have normalized or are normalizing. My platelets, which hadn’t been less than half of normal for years, are now a little over 100,000. Normal is about 150,000-250,000 or more. And my most recent CT scan shows continued shrinkage of my lymph nodes. You may remember that I had masses up to 16 (about 6-7 inches or so) centimeters in size in my belly and many others in my neck, underarms and so on. They are continuing to shrink, even after having been reduced to about 12% of their pre-treatment size after just the first three months on ibrutinib. No one can feel any masses any longer.

So, the clinical trial I signed up for was to last a period of one year. In the body of the multi-page “informed consent” which I signed there was a sentence saying that at the end of the study year, if I was doing well, I “may” be allowed to continue to take the drug. And, I have done so. Though I am now into my fifteenth month of ibrutinib, I am still receiving fresh supplies of it from the manufacturer, Pharmacyclics (in case you’d like a stock tip!) at no cost to me, M. D. Anderson or you taxpayers. I have asked how long they will continue to provide it to me, and other study patients, as I’m led to believe that the capsules, of which I take three a day, cost about $100 each. That’s about $100,000 a year.

But I’ve been reassured that as long as I continue to show up for exams on schedule and get my blood and bone marrow tested periodically, I’ll continue to receive the study medication at no cost. And that’s very important to me and the other folks taking this drug, because we have limited options at this point. If we go off the ibrutinib, the disease will be back very rapidly…because it really never left. Without the ibrutinib, I would only have a stem cell transplant to fall back on, with all its inherent deadly risks and side effects. But, having helped the researchers prove that this stuff works in the short term ( a year or so) I am now moving into a longer term study of the drug, helping to see if there are any serious side effects with longer term usage. And, just as importantly, finding out if the disease figures out this drug and develops a “work-around” to once again become aggressive. We also don’t yet know how long it’s safe to take the drug nor what, if any, more serious side effects may be lurking as the months and months add up for those of us lucky enough to be currently using this stuff.

But the side effects, at least in my case and in those of people I have corresponded with, who are also on the ibrutinib, are very tolerable. I still have occasional migratory joint pains and they continue to be primarily on my small joints, like fingers, hands and feet, but I have had a few days of significant pain in my left knee. But, thus far the large joint pain has been a one-time occurrence. I have had a couple of significant bloody nose incidents, but nothing I couldn’t handle with home therapy like pressure and rest, and one small bleed into the white of my left eye after rubbing it too hard or something. One drug side effect we know of is that ibrutinib inhibits our platelets’ function so you may tend to clot more slowly. This really hasn’t been a significant problem for me, however. I now tend to avoid the non-steroidal drugs like Motrin, Naproxen and such, to minimize any bleeding issues which those kinds of drugs can cause.

And as far as I can determine with all my questions, just about everyone that’s taking this stuff is doing well. That’s just incredible, that such a huge percentage of folks on this trial drug are doing extremely well. With most new drugs, if you see a 30% or 40% response rate, that’s considered pretty good. But to have an 80-90% response rate! Just amazing.

The drug is proving to be so effective that it is being “fast-tracked” by the FDA and may be available for widespread use by the end of this year. Already there are multiple “Phase 3” studies going on, comparing this new drug with older, more proven drugs. If it works better, or at least as well, without undue side effects, then it should be approved.

And there’s more good news for folks out there with other B-lymphocyte diseases. The ibrutinib is looking like it’s pretty effective in treating mantle cell lymphoma, Waldenstrom’s macroglobulinemia and a couple more diseases, too.

And if it turns out that ibrutinib can’t be taken indefinitely for my disease and others? Well, there’s more! In the last couple of years you may have heard of the new CARs process for treating leukemias and other diseases. First, however, a little explanation about what “CARs” really means…because it’s so much like science fiction.

“CARs” stands for “chimeric antigen receptors.” What researchers have been able to do is train a patient’s own white blood cells (the T lymphocytes, which are distinct from the B lymphocytes that make up CLL cells) to attack and kill cancerous cells. For ease of understanding it might be best to understand that the “T” lymphocytes originate in the Thymus gland, and kill tumor cells and viral diseases and the “B” lymphocytes originate in the Bone marrow and make antibodies. That’s not precisely correct but it may help you understand how they are different.

“T” lymphocytes normally try to rid the body of foreign materials, including tumors, like warts, for example. But cancers hide themselves well and look like normal tissue to the T cells so they aren’t attacked. What our wonderful researchers have done is to devise a way to make the T cells search out and kill any abnormal cells they find.

What they have done is reengineer the T cells by adding a modified HIV virus in a patient’s own T cells, which have been collected previously. This virus carries with it genetic information which has been added, making the T cells search for a specific protein receptor on the surface of the target cells; in this case, it would be the CLL cells. When the T cells have been modified, they are then put back into the patient from whom they came, and they go about their business, tracking down and killing CLL cells. This procedure was first performed by Dr. Carl June in Philadelphia a couple of years ago, and he made national headlines by apparently curing a couple of very ill CLL patients of their disease.

This is, however, very complicated and very, very expensive and labor intensive, as each treatment can only be used in one patient, the one who provided the T cells. So every patient has to have their own batch of modified T cells made.

This procedure has been used in a handful of patients so far, probably less than a couple dozen, I think, but there have been some dramatic results; some apparent cures of desperately ill patients and some significant improvements in others. But, there have also been patients who have relapsed and a few who have died, so it’s still not something everyone can, or necessarily wants to, sign up for right now. But, this technology is improving every year. The folks at M. D. Anderson are working on doing this procedure in the coming year or so and have an improved methodology in mind.

At the risk of going on too long about the CARs stuff, let me add one more thing, the difference between the early CARs procedures, as done by Dr. June and others, and then procedure that the researchers at M. D. Anderson have in mind.

The early CARs procedures trained the T cells to look for a surface receptor called CD19, which appears on all CLL cells. But the CD19 receptor, unfortunately, also appears on all normal B lymphocytes. So, the few folks who were treated with CD19 CARs cell have had their disease apparently eradicated, but those same wonderful treated T cells, which are hunting down and killing the leukemia cells are also hunting down all normal B lymphocytes, which make a person’s antibodies. So, their disease is gone, but now they can’t make antibodies. So, they are given IV infusions of what’s called “gamma globulin” on a regular basis. This is serum collected from the general population which is rich in antibodies.

Now, what the folks at M. D. Anderson are going to do is train the T cells to go after a different receptor, one with the enigmatic name of ROR1. This is important, as this receptor is only found on immature cells, like cancer cells and some other cells which are early in development. In theory, T cells modified to kill only cells with ROR1, like all CLL cells, should not also destroy normal B lymphocytes, our antibody producers. This will be a huge step forward in CARs therapy. This study is about to begin down in Houston, within the year, I believe.

I’m going to finish up by referring back to my last “adventure” message, in which I related how lucky I’ve been in getting where I am in my treatments for CLL. Many of you wrote back saying, essentially, that I had “made” my own luck, by my planning, researching and investigating options for treatment. And, indeed, in many ways I have been able to affect what treatments I have gotten and where I have gotten them. But I’m also lucky in whom I choose for friends, as I have friends and family all over the US and in Europe too, who are interested in what’s happening to me and many, many of these friends are praying for me on a regular basis. And they’ve added me onto prayer lists at their churches. This is important as I find it impossible to pray for my own health. Or to make deals with God, “If you’ll spare me, I’ll….” I find that seeming, somehow, to be selfish. I figure if I’m really worthy of prayers, others will intercede on my behalf. And, indeed, they have and look at the results!

So, I’m on autopilot for now, taking the ibrutinib at a dose of three capsules a day, adding up to what has rapidly become the standard dose of 420mg daily. I’ll be going back to Houston for another checkup in August to get some, hopefully, routine labs and an exam unless something changes between now and then. And if something does, I’ll be back with many more details than you’ll really care to read!


“You walk down the street and you feel intensely alive. You’re ‘Oh, look at that leaf!’ You’re looking around and you think, ‘I’m alive. Ain’t it amazing?’ ” --Wilko Johnson, former songwriter and guitarist for the ‘70s band, Dr. Feelgood, on how he feels since being diagnosed with terminal pancreatic cancer and having just months to live. He’s embarking on a, literally, a farewell tour. He says he has never felt more alive. “The 65-year-old musician says that in the weeks since his diagnosis, he’s been unexpectedly happy—‘In fact it amounted at times to euphoria. I suddenly found myself in a position where nothing matters anymore. I’m a miserable so-and-so normally…I’d be worrying about the taxman and all those things we worry about that get in the way of real things. And suddenly it doesn’t matter. All of that doesn’t matter.”