Ibrutinib; My Three and a Half Years on This Drug

Dave’s Great Adventure

Book 5, Chapter 2, Verse 11

[My apologies to anyone who has been trying to follow my story and who might have been wondering why I haven’t updated it in a while. I started to compose it (in my head) last March, actually started writing it in June, but then got distracted by some travels, some minor illnesses and, well, just being a bit lazy when it came to actually sitting down and writing. But, now I’ll get it done.]

June 2015

This story is getting pretty boring. But, that’s a good thing. Even a great thing, as that means things are going so well that there’s rarely anything to report that seems very interesting. I am way overdue in getting an update out and appending it to my on-line blog, but I just haven’t felt like there was anything of interest to report. But, now it’s been so long that I’m getting messages asking if I’m okay. And, there have been some changes, so an update is in order.

Last March of this year I celebrated two anniversaries. They were both very significant and the first was entirely the result of the second one.

The first anniversary I celebrated was that as of last March, I have been living with Chronic Lymphocytic Leukemia for 13 years! I don’t know if that sounds as incredible to you as it is to me. But when I first got sick and was diagnosed with CLL, I truly didn’t expect to live more than another 5 to 7 years or so. Many of you know that my father had the same disease and died within about five years. When he was diagnosed, back in 1976, there was no cure for the disease. And, 25 years later, when I was diagnosed, there STILL was no cure. I fully expected to be dead in a few years.

But many things have happened. I was fortunate enough, if I can use that term, to get this miserable disease at just about the time that multiple researchers were finding some more effective treatments. Not cures, mind you, but more effective treatments. Up until that time there were many good folks who advocated for not even trying to treat the disease. The feeling was that the patients would die within about 6 years, whether they were treated or not. So, the reasoning went, why torture them with treatments which aren’t going to help them live longer.

But, I was able to get a number of experimental treatments over the years that have kept me going for more than my expectations. I won’t go into the details, as they are all recounted in some excruciating detail on my blog postings, but I have been able to go from one new treatment to another, and just when it has looked like I was out of options, new options have appeared. I am one lucky guy. One of my friends in Miami says I have reminded him of a surfer who just keeps catching another wave when one runs out. Yeah, it’s really been something like that.

But that brings me to the second anniversary I celebrated in March. About four years ago I got some very, very bad news. I had been dealing with CLL for about 9 years at the time, and my treatments had been fairly successful at keeping the disease at bay for a few years at a time. That was at least in part because I had one of the more favorable chromosome types. This stuff is described in detail elsewhere in my blog, but there are at least five or more major different chromosome types among CLL patients, plus many other complex mixtures of chromosome types. I had, up until that time, a normal male chromosome type, the 46XY chromosomes. But, about four years ago I found that the disease had mutated to a different, much more deadly type called the 17p deletion (also described in detail elsewhere). With this mutation, which does not typically respond well to chemotherapy, my life expectancy was said to be 12 to 18 months, if untreated…and most treatments weren’t expected to work.

So, with my back against the wall, and with no good treatments to fall back on, I prepared for the only real option I had left, a stem cell transplant. Now, these transplants (also called bone marrow transplants) can be lifesaving and many folks are alive today only because they had such a transplant. But, and this is a big “but,” many folks have died from attempting the kind of transplant I would need. The death rate for a transplant from an unrelated donor is said to be anywhere from 25%-50% or so, depending in who you talk to. But, with no other options, I was evaluated in the transplant clinic at M. D. Anderson and signed all the papers to authorize them to start the search for a matching donor.

But, the very next day, which was in March three years ago (the other anniversary I celebrated last March), I was accepted into a clinical trial of a new drug, a drug so new that it didn’t even have a name, being called simply PCI 32765, its developmental code name. It had been tried on about 140 other very sick folks and seemed to be working very well for many of them, so I signed up to be in the trial, one of the next 40 patients to try this new stuff.. At the time, I was very sick, having large tumors in my belly, chest, under my arms and in my neck. But, within the first week of starting this new drug, which I was taking in combination with Rituxan, I could tell it was working. My swollen belly was shrinking and the lumps under my arms and on my neck were getting smaller.

And, for me, it has kept on working. I have now been on it for over three years, making me one of the patients who has taken it the longest. There are still about 90 folks out there who have been taking it for over four years now, but with every day, we’re making history, proving this stuff works and helping to find out how long it might continue to work.

It’s not a magic bullet for everyone, however. Of the 40 folks who were in my study group, within two years four had died. I don’t know if it was from disease progression (like Richter’s Transformation), bleeding or infection, or what, but 10% of my group is no longer with us.

The side effects have been, at least for me, fairly minimal. I have had intermittent but persistent pains in my joints, usually in the small joints of the hands and feet, but also sometimes in the larger joints as well; wrist, knee, hip, etc. The pains can be significant but are usually transient and last but a few days before disappearing. And I have days, many of them, when I feel significantly tired, even very, very tired. But there can be more serious problems. This drug, now called ibrutinib, and more recently approved by the FDA for general use and trade-named Imbruvica, can also cause heart rate abnormalities, most commonly a condition called atrial fibrillation, or A-fib. I have had two episodes of A-fib over the last year and a half, but both times the condition resolved on its own within less than 24 hours, so I didn’t have to be cardioverted, or “shocked” to restore a normal rhythm.

During the last two years, this medication has worked so well for me that my blood counts are near-normal, with my white blood cell count being about 5,000 at every monthly blood test (normal is about 3,000 to 10,000 or so). So, since my counts are staying normal, and because I am having, at least intermittently, a significant side effect like the A-fib, Dr. Keating has reduced my dose of ibrutinib from the usual three capsules daily, to just one capsule daily. We’ll see how my counts look after a month or so and see if I can stay on the reduced dose or whether I might need to go up to two capsules daily.

As an aside, I should mention that when this drug was first studied in the very first 140 patients, the researchers were comparing a dose of six capsules daily against a dose of three capsules daily. They found, early on, that three worked just as well as six, and caused fewer side effects, so all patients from that time on were given the lower, three capsule dose, which is what I was started on.

However, no one, to my knowledge, has done a controlled study to compare how effective one or two capsules are compared to the standard three daily capsules. I know that since the drug has become more widely available, after the FDA’s approval last year, many folks or their docs have tried reduced doses of the ibrutinib. In fact, one of my CLL “pen pals,” who was having horrible rashes with the drug, completely on his own, and not even at his doctor’s recommendation, reduced his dose to two daily and his blood counts have continued to improve over the last year, even though he had very high white blood cell count numbers when he started on the drug. Dr. Keating noted to me that he has a number of folks on reduced doses, many even as low as the one capsule daily that I am now getting.

This could be significant on many fronts. First, if this lower dose works as well as the three capsules a day, then one could expect fewer side effects with no apparent reduced efficacy. Secondly, this drug is VERY expensive. The list price for ibrutinib is $92 a capsule in the USA, or $276 daily. That’s close to $100,000 a year. If patients could be eventually maintained on just one capsule daily, that would be a significant savings for the patients and their health insurance providers.

I’m happy to have been so stable on the ibrutinib, as I truly think it has saved my life, but while I’m doing well on it, I am having some other issues. Anyone who is diagnosed with CLL is told, early on, that they are now at increased risk for a second, or more, malignancy. For men, the greatest risk is for skin and prostate cancers. Well, a couple of years ago I developed a skin cancer, a small squamous cell carcinoma of my left forearm. It was easily taken care of but now I have to get twice a year full body checkups from my dermatologist.

But, more recently, my blood test level for my PSA (prostate specific antigen) has gone up, more than double last’s number. A visit with the urologist revealed a possible small irregularity of my prostate. But, a repeat blood test a few weeks later showed that the blood test had returned to normal levels. I just had a third test and will see the urologist yet again in a couple of weeks to see where the level has gone. It looks, however, like I’m going to have to have some prostate biopsies to see if I have a prostate cancer, or to prove that I don’t. I don’t really care for the idea of the biopsies, but it probably shouldn’t be TOO big a deal. I hope.

September 2015

Okay, I’m back and I’m going to finish this up. But first I need to update the “updates,” as things have changed yet again. First, let me follow up on the prostate issue. Since I wrote all this I have had a series of prostate tests and the levels have gone down, down and down, to completely normal levels. This has happened after a couple of courses of antibiotics, so one presumes that the cause of the abnormal PSA tests was a mild prostate infection. So, no prostate biopsies yet, and I’m to get another PSA blood test next January followed by an exam. Hopefully all will still be normal.

Secondly, the trial of taking just one capsule of the ibrutinib daily didn’t last very long. After one month, my white count was up to 6,700. Now, this is a completely normal number for most folks, but my white blood cell counts had been consistently between 4,500 and 5,500 for the last two years or so on the standard, three capsules daily dose of the drug. So, the rise to 6,700 might have been significant. I reported this result to the folks at MDA and I was put on an increased dose of two capsules daily, about five weeks ago.

But, just as I was starting this new dose, I got sick with a cold which progressed to a bronchitis. I’ve been coughing for several weeks now and finally started some antibiotics when I was well past the usual viral stage of the cold but was still coughing. So, last week, when I got my next blood counts done, my white blood cell counts were up to 10,400, a major increase. Now, this is still a normal number for most normal folks, but it’s higher than I’ve been in a few years, since I started the ibrutinib. The question is, did the white count go up because my CLL is no longer well-controlled at the two capsules a day dosage, or did it go up because of the bronchitis. After a bit of discussion with the folks at MDA we decided it was most likely the result of my infection, since bacterial infections can elevate your white counts, as they go to work trying to kill off the invading bacteria and such. We’ll see if the counts are still elevated when I get my next blood test done at the end of September.

I have mentioned, in the past, about the possibility of getting a CAR-T procedure, the “chimeric antigen receptor-T cell” procedure in which one’s own T white cells are harvested and modified to fight leukemia cells. It has been used in some small studies around the country with varying success, but it’s not yet ready for prime time, I’m afraid. In fact, the MDA CAR-T tests have gone off the rails. It appears that a large pharmaceutical company hired away the lead investigator and then gave MDA a large grant, and in doing so, created a conflict of interest which MDA’s lawyers are looking into. So, for now, CAR-T is not looking like it will be an option in Houston for a while.

But other therapies are coming on strong. First, there have been a couple more oral agents approved for CLL. This gives us more and more options for treating the disease, even if one of the drugs (like ibrutinib, as an example) fails, there are others to go to, like ABT 199, now known as Venetoclax. There are several patients who have been on ABT 199 until they achieved a complete remission and then, very bravely, stopped the medicine. In at least the several months since they went off the drug, the disease has failed to return. This is amazing.

And just as exciting, I think, is the advancing of the Immune Checkpoint Inhibitors. We have known for a while that in CLL and other cancers, the body’s own immune system fails to control the disease as it should. Researchers have found that there is an inhibitor on the surface of the patient’s T white cells, the ones that normally search out and control abnormal cells like cancers, and this prevents the T cells from doing their jobs properly. But, now antibodies are being developed which block this immune inhibitor, turning the cells loose against the disease. This process has been used successfully against several solid tumors, like melanoma and renal cell cancers, and the thought is that these antibodies should work well against CLL cells as well. We shall see. I’ll probably talk about this a bit more in an upcoming message.

I want to finish up with the mention of one more anniversary I’ve had recently. Last month Kathy and I celebrated our 46th wedding anniversary. That’s another truly amazing anniversary, as when I first got sick, I really didn’t expect us to be able to celebrate our 40th anniversary together. But, now I’m doing so well, and there are so many wonderful new treatments for CLL, that I’m beginning to think I’ll be around for our 50th anniversary. This has been an important union for us, and I couldn’t have gone through all the trials of dealing with this disease without Kathy at my side. She’s been with me every step of the way and has sat by my side, hour after hour and day after day as I was getting chemotherapy and feeling sick afterwards. It’s so wonderful to have her to rely on. And, we’ve had so many wonderful friends throughout this journey who have also given us support, love and prayers all these years. We have been truly fortunate.

And this has gotten too long…again…as my stories always do. But I’ll be back when there are any changes in what’s going on and maybe I’ll be able to be just a bit more concise in my writing.

Dave

“Life must be understood backwards. But it must be lived forwards –Soren Kierkegaard

PS: If you’re the praying kind, please take a moment to remember our friend and fellow TNT Teammate and Honored Hero, Doug Campbell and his wife Stacey and their daughters, in your prayers. Doug has been in Team in Training for many years and completed many distance events with the team, raising money for the Leukemia and Lymphoma Society even while battling an aggressive, incurable lymphoma. Several years ago, when he exhausted his chemotherapy options he began looking at a stem cell transplant, but a good match could not be found. His family organized many bone marrow donor drives, which will likely help many other folks in the future, but still a good match for Doug could not be found. Finally, about four years ago, I believe, a partial match was located. It wasn’t great, but it was all that was available and Doug needed treatment desperately. So, he underwent the transplant but very soon afterwards began having significant Graft Versus Host Disease (GVHD) complications, wherein the transplanted cells attack the patient’s organs. Doug has battled valiantly for several years now, getting through one crisis after another, with Stacey ever by his side. Ironically, the transplant has cured his “incurable” lymphoma but its side effects are beating Doug up badly. Now Doug is in severe heart failure, has compromised lung functions, diabetes and more, and is not doing well. He was offered the possibility of a heart transplant, but has decided that enough is enough. He has decided to forego further treatment, having fought the good fight for so many years now. His family hopes to get him home so they can be together for what precious little time he has left. He is a wonderful guy and is deserving of your prayers and so much more. Godspeed, Doug.

My Two and a Half Years on Ibrutinib

Dave’s Great Adventure
Book 5, Chapter 2, Verse 10
November 7, 2014

I’ve been taking that near-miraculous drug, ibrutinib, for about 30 months now. I believe it has, quite literally, saved my life.

Just a little over three years ago I got very bad news. The CLL I had been fighting for nine years had mutated from a moderately aggressive form to the most aggressive form of the disease. I found that I had the dreaded 17p deletion, wherein my chromosomes had lost a gene called the “tumor suppressor” gene. Without it, the disease is very aggressive and especially resistant to chemotherapy. Most studies predict that without treatment, the expected longevity with this mutation is between 12 and 15 months or so.

The only treatment really known to work in this circumstance is a stem cell transplant (or bone marrow transplant; they are the same thing), which I knew would be a possibility at some point in my life, when nothing else was working for my disease, but I wanted to postpone a transplant for as long as possible since a transplant is not without risk. There is a fair chance of dying from the procedure, and this risk is generally quoted as being about 25% or so, depending on whom you talk to and where the procedure is done.

My doc at M. D. Anderson in Houston tried to treat my disease with a newly approved medication called Arzerra (ofatumumab) for a few months to see if it might work. But after four monthly treatments, it was clear that it wasn’t working. A CT scan showed that I had multiple tumors in my belly, chest, neck and underarms, the largest ones being about the size of oranges. It looked like it was time to see about that transplant, and so I did. I went to the transplant clinic at M. D. Anderson and was examined, filled out all the questionnaires, gave multiple tubes of blood and signed forms agreeing that I knew the cost could be upwards of a million dollars, which I would be responsible for if insurance didn’t cover it. Yikes!

But, the very next day I got wonderful news. I had been accepted into a Phase 1/2a study of a new drug, a drug so new it didn’t yet have a name. It went simply by the name PCI 32765. It had been tested recently on about 90 seriously ill folks with CLL and seemed to show great promise. I jumped at the chance to get into the study.

I began taking this drug, the first of its kind, and an orally active medication for CLL, in April 2012. My previous treatments for my disease, over the previous years, had all been IV chemotherapy, needing four to six months of therapy, several times every four weeks. But this PCI 32765 stuff…it was so easy. Three capsules in the morning and I was done each day.

When I started my treatments with the PCI 32765, it was in combination with Rituximab for the first six months. By the time I was able to start taking my first doses, the tumors in my belly had grown to be about 16 centimeters in diameter, about grapefruit sized. I looked pregnant. My belly was distended with tumor, I had large lumps in my armpits and had multiple tumors on the sides of my neck. I was very sick. But, within the first week of starting on the Rituximab and PCI 32765 combination, even before I was examined again at the clinic, I knew it was working. Within days I could tell that my belly was less distended. The tumors were shrinking that fast!

Indeed, when I had a follow-up CT scan three months after starting the ibrutinib (as the generic name of PCI 32765 came to be called) the tumors had shrunk by almost 90% of their volume. Within a year, the tumors were gone. During that time my white counts came down to normal, my red cell counts improved and my platelets stayed steady, though lower than normal, as they had been since my third round of chemotherapy in 2008.

The side effects of this near-miraculous new drug were, at least in my case, almost trivial. I had frequent pains along my joints, primarily in the small joints of the feet, hands, wrists and ankles. This was often accompanied by some redness, and the pain could be significant but almost always resolved within three or four days. Rarely did I take any medications for the pain. I also had some very minor skin rashes, a few small sores in my mouth on occasion, but not too much more. I have the fatigue that most folks with CLL seem to have, and I have all too frequent sinus infections, which are also very common, but that’s about it. Now, I know that other folks have had very serious, full-body rashes and more severe pains, some have had significant diarrhea, and some have had sloughing of their mucous membranes in the mouth and other places. But, I have been exceedingly fortunate in having so few symptoms. And, I think my experience is probably more typical than that of those folks who have had worse problems with side effects. In any case, the side effects are significantly less than could be expected of a bone marrow transplant. This is one amazing drug.

But, it’s not perfect. As I’ve mentioned, there is a small failure rate for some of us on this drug, mostly among the people like me with the bad mutation, the 17p deletion. But, I’ve been told it’s only about a 5% failure rate, with a few other failures occurring in the 11q deletion patients and a few others as well. Apparently some folks have developed a more serious form of our disease, with Richter’s transformation, where our disease transforms into the much worse “diffuse large B cell lymphoma” (DLBCL). So, ibrutinib is not a perfect drug, but nothing is when you’re treating cancers of any kind. But, man, is it good. I’ve been in contact with many folks all over the world and all of them who have started taking ibrutinib, except one unfortunate guy who developed DLBCL, are doing just great.

Initially, when starting the Rituximab and PCI 32765 treatments, we were going to Houston weekly. After five consecutive weeks, the frequency was reduced to monthly for the next five months. As my exams and labs began to normalize, the appointments went to every three months, then every four months…and at my last visit in August, after my two and a half years on ibrutinib, they told me to go away and not to bother them again for SIX months, sending me off with a supply of ibrutinib worth more than the car I was driving! I continue to take three capsules daily and the list price per capsule, now that it has been approved by the FDA, is about $92 each. So, six months’ worth of capsules is indeed worth a fair amount.

Kathy and I have been taking advantage of my/our good fortune and, after this excellent news, went on a 16 day river cruise in Europe, passing through Germany, Holland, Austria, Slovakia and Hungary. This was a very, very nice cruise and, despite having lived in Germany for seven yeas while I was in the Army, we saw many cities and places we hadn’t visited earlier in our lives. And, life for us has returned pretty much to normal again. The only continuing problems I have are the intermittent joint pains and the enduring fatigue. But, those are very small prices to pay for having access to this incredible new drug.

The standard three capsule daily dose is something several folks have been looking at. When this drug went through Phase 1 and Phase 2a studies, the only doses studied were 840mg and 420 mgs daily (six or three capsules a day). It was quickly found the three capsules work as well as six, so the larger dose was dropped. But, to my knowledge, no one yet has studied any lower doses. Doc Keating has mentioned wanting to study the efficacy of lower doses, and to study leukemia cell receptor saturations at lower doses, but the drug was controlled by the company and human use studies are exceptionally difficult to get approved. As they should be.

But now that the drug has been FDA approved, is widely available and can be prescribed by any physician, I know that there are people who are trying lower doses. I have a correspondent who, on his own, lowered his dose from three capsules daily to two because he was having horrible full-body rashes. His rashes have improved and, in the short term, his blood counts seem to be continuing to improve. And I have heard of another patient who was refusing any chemotherapy of any kind, who was convinced to try just one ibrutinib daily, and also in the short term, I hear that she is improving. Time will tell what the optimal dose will be. I keep expecting to hear of a clinical trial with one, two and three capsules a day, to see if they are, or are not, equally effective.

Meanwhile, the FDA has approved yet another oral drug, idelalisib, for use in CLL. And there are more in the pipeline. The stuff called ABT 199 is showing great promise and should be coming along soon. It’s the drug that Doc Keating said I may be switched to if I relapse while on the ibrutinib.

But, even as these first generation drugs are being developed and approved, there is now a second generation drug like ibrutinib (another BTK [Bruton’s tyrosine kinase] inhibitor) in trials. This drug is called ACP 196 and it is in Phase 1 trials in multiple centers right now, including at M. D. Anderson.

In other recent notes about this wonderful drug, I have recently heard news that makes it much more convenient to take. Originally we were given strict instructions to take it on an empty stomach, at least thirty minute before we ate, or two hours afterwards. But recently one of the researchers has said that the absorption is the same with or without food in your stomach. It just seems that there is less diarrhea when taken on an empty stomach. Since I’ve never had any issues with that at all, I now just take my capsules in the morning with breakfast. And, I’ve mentioned the CARs procedures in previous messages, where one’s T lymphocytes are modified to attack your leukemia cells. The folks at M. D. Anderson have been working on a specific type of CARs (or also called CART) called the ROR1 CARs. But, as of my last visit, it still hadn’t gotten into clinical trials, so I don’t think that possibility will be in my future any time soon. But, work on this is slowly progressing.

When I started this series of little stories, they went out solely to family and close friends, and though I had a fairly long mailing list, it was limited to about 150 folks. But, just a few years ago our kids convinced me to publish my messages in an on-line blog form, to make them easier for my friends and family to access. And this has had an interesting unintended effect! Other folks around the English speaking world, when Googling “ibrutinib” or “CLL” and other topics, have stumbled upon my stories and I have had contact with many other people with this disease, or the family members of folks with CLL. I have correspondents in England, Canada, Australia and across the USA. My stories have been read, on-line, by hundreds and hundreds of people. I know this because Google, who runs the blog site, keeps track of every click on my stories.

It has been a wonderful thing to share our stories with each other and to be able to commiserate when we had to. I have shared my experiences with lots of folks and have tried to judiciously dispense advice about what might be available and/or advisable for others with this disease. But, I’ve had to put a disclaimer at the top of my blog, noting that I’m really not an expert. I know, or at least I think I know, a lot about CLL as I’ve been dealing with it, reading about it and writing about it for almost 13 years now. But, I have to tell you, when I start talking with Dr. Keating about the details of CLL, or when I get into the research articles about CLL that are published in the hematology/oncology journals…I admit that I have trouble understanding a lot of it. And so, I can fully appreciate how non-medical folks would have difficulty comprehending so many of the details of this very complex disease. So I am very happy to try to help other folks understand what they are facing and what their options are. It is nice to be able to tell them now, after many years of having little real hope, that we live in a “golden era” for patients with CLL. There are now so many very effective and non-toxic options for us. Most of us shouldn’t have to have harsh chemotherapy and most of us should be able to avoid a stem cell transplant and its attendant risks. A cure is surely coming soon.

And, so, that’s all for this episode. I’ll be going back to Houston to be examined and have another bone marrow biopsy in January. My monthly labs tests done here at home have been completely stable and so I’m fully expecting that my check-up in January will be normal as well. If so, I’ll probably be continuing on the ibrutinib, as long as it keeps me disease-free. The manufacturer has agreed to keep its early test subjects supplied with the drug as long as we are willing to be examined periodically, as they need long-term data about its effectiveness and side effects. So far, we only have about four years’ worth of data on a few hundred patients. It’ll be nice when we have, maybe, ten years or more of data to show that it keeps on working for many, many years.

Here’s hoping!

Dave

“Take therefore no thought for the morrow; for the morrow shall take thought for the things of itself. Sufficient unto the day is the evil thereof.” Matthew 6:34

“I have told you these things, so that in me you may have peace. In this world you will have trouble. But take heart! I have overcome the world. ” John 16:33

About that transplant...

Dave’s Great Adventure
Book 5, Chapter 2, Verse 8
July 7, 2014

Dr. Keating came into the exam room and sat down. Then he leaned a bit toward me and smiled the impish smile he often has when we’re talking. “Don’t worry about those terrorists over in the Transplant Clinic,” he said, with his Australian accent.

I had expected to have to make a major decision about a transplant soon, probably at my visit in May. I even had an appointment to see the very kind folks at the Transplant Clinic which had been on my schedule for three months. Each time we get to M. D. Anderson on the morning of my appointments, I always ask for a printout of those appointments to make sure none of the times has changed. But this morning when I got the printout of my appointments and times, the appointment at the Transplant Clinic had disappeared. I was surprised.

So, I got my blood drawn as scheduled and then went to the Leukemia Clinic to await my appointment there. I saw Jackie, as I usually do, and she went over my history and did the usual physical exam. All was well. My labs tests were all stable and my white and red blood cell counts were normal. No evidence of relapsing disease. I told her that I was puzzled about the missing appointment at the Transplant Clinic, as I had expected to be talking about the possibility of a transplant in the fairly near future.

So Jackie completed her exams and questions and left the room, leaving me to await Dr. Keating’s time with me. And that’s when he came in and told me that a transplant wasn’t very likely in my immediate future.

Things are going too well, he said, to think about doing a transplant right now. My marrow seems devoid of disease and my labs and exams are all normal. So, with that subject off the table, I asked some questions I had, questions which had been lingering in my mind, bothering me about what might lie ahead. I had been especially worried about the problem of folks like me with the 17p deletion failing the Imbruvica therapy. I asked, what percentage of us are failing the therapy so far. I had been told only that it was “common” in the past, but had no idea what the magnitude of the failures might be. What was it, I wondered; 80% of us, 50%, what? No, he said, it’s more like 10%, which I found reassuring because, I’m sure (as we all are, of course) that I won’t be in that 10% group. So then I asked, of those who 17p deletion patients who have failed, how many have died. Well, none of them. They are getting treated with various other therapies; some with ABT 199 (another drug in the Imbruvica category), Arzerra (similar to Rituxan but more “humanized”) and other things. Probably some have had transplants, too, but I failed to ask about that. And that I found to be very reassuring. I also asked about how the disease came back when folks relapsed, as I had wondered if it came back as Richter’s or worse. Yes, it does some times, but that apparently is not seen routinely. So, it seems like there is still a lot of good news about this drug and my continued treatment with it.

We moved on to talk about the CARs (chimeric antigen receptors) studies being done at MDA. I have mentioned this new procedure in some of my previous stories, but I’ll touch on it again just briefly…if I can actually be brief! This is the procedure wherein one’s T-lymphocyte white cells are harvested, much like donating blood or platelets and such. But then the patient’s T-lymphs are treated with a modified retrovirus, like an HIV virus, to insert a gene into the DNA of the patient’s lymphs. This gene will do a couple of things. First, and most importantly, the T-lymphs will be modified to search out cells with a specific protein on their cell membranes. All CLL leukemia cells have a protein called CD19 on them and the early studies of CARs have looked at teaching the T-lymphs to kill cells carrying this protein. The second thing that the T-lymphocyte white cells are taught to do is to reproduce when they find and kill such a cell. There have been some notable successes with this approach, including a very few folks who are now, apparently, cured of their disease. But, there is a problem with this approach. Although all CLL white cells carry the CD19 protein, so do all normal B-lymphocyte white cells, and they are the cells that ultimately make your antibodies so you can fight off infections. So, although a few folks have been cured of their disease, they must frequently get infusions of antibodies, gamma globulin infusions, since they can’t make their own antibodies.

The folks at MDA are taking a different approach. One of their colleagues in Sweden discovered a protein on CLL cells called the ROR1 protein. This protein is generally found only on certain malignant cells and a few immature cells. It is not found on normal B lymphocytes. So, if one’s T-lymphs could be modified to search out and kill only cells with the ROR1 antigen, then the problem of the normal B-lymphs getting caught in the crossfire might be solved, along with the problem of not making one’s own antibodies. By the way, ROR1 is also found on kidney, breast, lung and colon cancers, so this could possibly have applications beyond the treatment of CLL.

But there are folks who say they’ve found the ROR1 antigen on other tissues like fat cells, pancreatic cells and such. If that’s correct, and the ROR1 protein is found on these tissues in significant quantities, then it might not be good for the patient. Even if you think it would be okay for your T-lymphs to gobble up your fat cells, the problem could be that they would destroy massive amounts of the cells and the cellular debris could clog up your kidneys, causing “tumor lysis syndrome.” That’s not good at all, and can be deadly. But this problem, if it exits at all, does not seem to be a serious issue in the early going. So, the researchers at MDA have started this process with a very few patients so far. I really don’t know if we’re talking about one or two folks, or if they’ve tried it on six or eight. I just know it’s not many yet. That’s for a couple of reasons.

First, just doing this is very labor intensive, as you can only make one batch of cells for any given patient. My cells, for example, wouldn’t work for anyone else. These things can’t be mass produced in large quantities. So each patient will have his or her own personalized batch of T-lymphs made up for them.

The next reason it’s going slowly, is that it’s a very new process, and as with most very new medical processes, it’s generally tried out first on the folks who are the sickest and have no other options. Therefore, folks like me, who are currently doing well on the Imbruvica, are not really great candidates for a process which has not yet been proven to be effective. So, we’ll see how it goes with the early studies and will hope to see great results without too many complications. If things go well in the study, I may be a candidate somewhere down the road as data is collected on the pioneers of this procedure. Doc Keating says I don’t want to be the first candidate for this new procedure, but that he’ll let me know when they’ve done ten or so with good outcomes!

By the way, all this research on the ROR1 CARs is being done in conjunction with the Transplant Clinic folks, so it’s possible that they are in on the plan to eventually try to get me into the study, and that may be why my appointment with them at my last trip to Houston mysteriously disappeared.

While we’re talking about ROR1, let me also mention that other researchers are working on creating ROR1 antibodies which can be given by injection/infusion to attack CLL cells. This would be very much like the Rituxan I’ve had several times, but would not (like the Rituxan does) affect normal B lymphs cells along with the bad guys. This would have to be given repetitively, like Rituxan, and would not be a cure, as the antibodies would eventually disappear from the patient’s circulation. The advantage of the ROR1 CARs therapy is that it could, in theory, be a cure if the ROR1 treated cells persist indefinitely, continuously seeking out and killing CLL cells wherever they find them. Cool stuff!

So that’s where we are right now. I’ll continue to take the ibrutinib/Imbruvica for the foreseeable future, as long as it keeps working for me and as long as my disease doesn’t find a way around its effects. And we’ll keep an eye on the research being done on the ROR1 CARs procedure, to see if I might ultimately be a candidate.

Until the next time, after my visit to Houston in August.

Dave

“Work for a cause,
Not for applause.”

It's Your Choice

Dave’s Great Adventure

Book 5, Chapter 2, Verse 7

“It’s your choice,” said Dr. Khouri.

I’ve been riding the CLL roller coaster for twelve years now, and count myself as very fortunate to have been able to do so. Lots of folks with CLL don’t last this long. I’ve had some very low lows and some very high highs on this roller coaster, but among the highest times I’ve had was when I was accepted, almost at the last minute, into the ibrutinib with Rituxan trial at M. D. Anderson in Houston a couple of years ago.

I had just found out, a few months before, that I had developed the deadly CLL mutation called the 17p deletion, or the p53 deletion. They’re the same thing and they refer to the fact that my leukemia cells have mutated and have lost a part of my number 17 chromosome, the part which contains the gene (the p53 gene) which makes abnormal cells self-destruct when damaged. That gene is why chemotherapy works. The chemotherapy damages the cell’s DNA and so the p53 gene makes the cell die. Without that gene the abnormal cells continue to grow and are almost entirely resistant to chemotherapy, making the disease very hard to treat.

After we found that I had developed this mutation we tried some new chemotherapy but it didn’t work. I was developing very large tumors (enlarged lymph nodes, really) in my belly, under my arms, in my neck and in my chest. They were up to the size of a cantaloupe. With chemotherapy no longer working, I was just about out of options. All that was left for me in hopes of treating the disease was a stem cell/bone marrow transplant.

I’ve known since I got sick twelve years ago that a stem cell transplant would be my ultimate safety net when nothing else was working. But I’ve been extremely fortunate to have been able to ride the wave of new treatments and experimental studies from one relapse to the next and have never had to seriously consider a transplant. Now, a transplant can be curative and has cured many folks, but it’s something most folks only go to when they’re out of other options. That’s because the usually quoted death rate from a transplant, of the kind I would need, is about 25% or about one chance in four of dying from the complications of the transplant. Scary! And even if one survives the initial transplant, there is the very real possibility of long term problems with what’s called “graft versus host disease.” That’s the opposite of a person rejecting a transplanted organ. In the case of GVHD, the transplant is “rejecting” the person and it can cause anything from minor annoyances to major problems including death.

But, two years ago I was facing this decision. I had the deadly mutation, the 17p thing, and I had failed my last ditch chemotherapy. I was out of options. So, Kathy and I were in the Stem Cell Transplant Clinic at M. D. Anderson in Houston, signing me up for one. None of my siblings match me, so the best I could hope for would be an inelegantly named Matched Unrelated Donor transplant, or “MUD.” We signed all the paperwork and set the wheels in motion for a transplant in the coming weeks or months, once a suitable donor could hopefully be found.

But, the very next day I was accepted into the new ibrutinib study! And so we put the transplant on the back burner while we waited to see how I would do on this new drug, which was so new that at the time it had only been tested on about 90 other folks, worldwide, and didn’t even have a name. Back then it was called PCI 32765, its developmental code name. Since then it has acquired a generic name, ibrutinib, and more recently, a trade name, Imbruvica.

And I have done incredibly well on this new drug. I take three capsules daily (at a cost of $91 per capsule or $273 a day) and I could tell within days that it was working. I could feel the swollen nodes shrinking and my swollen belly getting smaller. When I started the drug 90% of the white cells in my blood were leukemia cells, and 60% or more of the cells in my bone marrow were leukemia cells. But, I had a bone marrow biopsy just a couple weeks ago and, incredibly, there is no evidence of leukemia remaining in my bone marrow! This is just amazing news.

But, as more people have started taking this near-miraculous drug, and as the early participants have been on it longer and longer, the researchers are finding that many (or perhaps most… I really don’t know for sure) of the patients with the 17p deletion (and some with a few with other chromosome types, too) seem to be failing the drug after about 30 to 36 months on it. I’ve now been on it for about 24 months.

That brings up a dilemma for me. I’m still doing just great on the drug and am taking it daily with minimal side effects. But, if the experience of the folks who have been on it longer than I have applies to me, we might expect that I, too, will fail the drug and have a progression of my disease within the next year. And if I do, what would be the next drug to try? Well…no one knows. There are lots of new experimental drugs out there which are being tested on various groups of patients with CLL, but there is no known therapy which is “best” for people who have failed the ibrutinib. Anything we might try would be a shot in the dark. There just isn’t any data that I know of, indicating what might work. That is, if anything at all will work.

Meanwhile, I’ve been going back to visit the stem cell transplant folks periodically, about every three to six months or so. The visits have pretty much been of the “Hi, how are you doing, see you back in three (or six) months!” variety. But it seems they’ve been following my progress more than I realized. They know that I have the p17 deletion, and when they learned that those of us with that particular chromosome type are beginning to show signs of failure on the ibrutinib, they knew, before I did, that I might need a transplant in the near future. So, they went out and completed the search for a donor for me. And now they have one lined up, apparently.

So, going back to the bone marrow biopsy I had recently, the one which didn’t show any leukemia at all. It seems that now that I’m in clinical remission, with “clean” bone marrow, I’m in just about optimal condition for a stem cell transplant! That’s quite a dilemma for me, as I feel and look normal right now and don’t feel like I’m so sick that I need to take a chance on a stem cell transplant. But, I’m told that if I wait to see if/when I relapse, I’m likely to develop a more aggressive form of the disease and it could be more difficult to have a successful transplant. Dr. Khouri, in the transplant clinic (one of the pioneers in the field, by the way) is strongly urging me to do the transplant now rather than waiting. But, as he said at our last visit, after explaining the risks of waiting, “I think we should do the transplant now, or we can wait and see what happens. It’s your choice.”

So, that’s my dilemma. Get the transplant now and take a chance on the known risks, or wait to see “if” I relapse and take a chance of having a lower chance of a successful transplant at a later date. I’ll wait at least a couple of months until I see Dr. Keating again in May, when I’ll present him with my laundry list of questions and decide, as best we can, what I should do right now. And, if I don’t go the transplant route now, what he thinks might be my next steps in treatment if/when I fail the ibrutinib.

Meanwhile, there’s more news about ibrutinib, which is now called Imbruvica. In mid-February it was approved by the FDA for use in patients with CLL, but the approval was for patients who have failed at least one prior mode of therapy. In other words, you have to go through chemotherapy at least once and fail it before you’ll be approved for the less toxic Imbruvica. That’s counter to what the CLL experts are wanting to do as I believe they would like for everyone to be able to avoid chemotherapy entirely. That’s because chemotherapy damages cells and suppresses immune systems. Hopefully, Imbruvica will eventually be available for anyone who needs it as their front line therapy.

And that’s the story for now. We’ll have to decide fairly soon whether I’ll be going for the transplant or whether we decide it would be safe and not unreasonable for me to wait a while longer to see how I do on continued Imbruvica therapy. And see if a logical and effective follow-on treatment shows up. More later…probably in May.

Dave

Ibrutinib Update

Dave’s Great Adventure

Book 5, Chapter 2, Verse 6

I’m still doing fine but a lot of news has recently come out about the new, experimental drug called ibrutinib, so much so that I thought an update on it and other related topics is needed. This will be more of a technical update than a personal one.

First, and foremost, the FDA has approved ibrutinib to be sold on the open market and not just to be used in clinical trials. But, quite surprisingly, to many folks at least, it was approved, not for chronic lymphocytic leukemia (CLL) as expected, but rather for a rare and aggressive disease called a mantle cell lymphoma, about which I know very little. Approval of the drug for the treatment of CLL is still expected in the coming months, but with its approval for mantle cell lymphoma (MCL), that is almost a moot point. With the drug on the market now, physicians are pretty much free to use it as they want by using it “off label.” That means they can use any approved drug for other diseases if they feel there is a benefit. There are many examples of off-label use in medicine, such as antidepressants used for peripheral neuropathy, narcotics used to slow down over-active bowel function and many, many other examples. I have already heard of one patient who will now be getting ibrutinib for her Waldenstroms macroglobulinemia, for which the drug is showing great promise. But, I don’t even know if the company has applied for permission to be used for this disease. No matter. It’s now on the market.

And, now that it’s more widely available, it has a trade name. When I first started taking this drug it was still going by its company’s in-house development code, being called PCI 32765. Then, a few months later it was given its current generic name, ibrutinib. But now it has an official trade name of “Imbruvica.” And with that name comes its current marketing price, $91 per capsule. Those of us with CLL take three capsules a day, which comes out to about $8200 a month, or close to $100,000 a year. I believe the folks with MCL actually take four capsules daily but I can’t be sure of that.

And much more specific information is now available about how it, and many other drugs and procedures, are working against so many blood cancers and lymphomas. The American Society of Hematology recently concluded its meeting in New Orleans and all of the abstracts of the hundreds of presentations are now available on-line, for your review. It includes many interesting findings and nuggets of information, with a great deal of information about new and novel treatments for CLL. If you’re interested in taking a look at all or some of the abstracts, look here:

https://ash.confex.com/ash/2013/webprogram/start.html

There is a search function which will allow you to search out the topics of most interest to you. I have to warn you, these are specialized topics written in the lingo of the specialists and some of the data are hard for us amateurs to decipher.

But there are several abstracts (which are just summaries of the presentations, not the entire article) which are of great interest to me. First, Dr. Jan Burger, who is the lead investigator of the study I’m in presented the official findings thus far. You can see it here:

https://ash.confex.com/ash/2013/webprogram/Paper58781.html

I learned a great many things. As I have stated several times in my updates, when in Houston I generally ask how the other 39 folks in the study are doing. I am routinely told that everyone is doing fine. But, I don’t know if I’m asking the question too generally, or if the answers I get are just too general, or if (probably) the folks I’m asking just can’t tell me about the other study participants. But, what I have learned is that all of the other patients in the study are NOT doing just fine. In fact, of the forty original patients in the study, four are now dead. They are reported to have died of unrelated infections; sepsis, pneumonia and cardiovascular failure. Further, four more dropped out of the study for other reasons; two for ibrutinib related complications like mucositis (inflammation of the mucous membranes in the mouth, bowels, etc.) and a subdural hematoma (remember that ibrutinib inhibits platelet function and the clotting process), another with disease progression and one left to have a stem cell transplant. I have to assume, but do not know, that the person who left to have the stem cell transplant must not have been responding well.

However, despite these problems in eight of forty patients in the study, we have to remember that the study recruited the sickest of the sick. All the patients in this study had very bad prognostic indicators. Most had the 17p deletion, the 11q deletion and/or had failed multiple other therapies. Despite the loss of some of our group, the study reported a 95% overall response rate (complete or partial remissions) with 80% of us remaining on the drug without disease progression after 14 months or so. This is still a remarkable response rate in folks who are very high risk and, essentially, have no other options except that of a stem cell transplant.

If you look at this paper, it mentions that most of the study subjects were IGVH un-mutated. If you’re looking at this message you likely know that having the IGVH mutation is considered a very good prognostic sign, so it’s not much of a surprise to see that most of these patients in the study, who are generally pretty sick, do not have the mutation. However, note that Dr. Burger says one patient does have the mutation. Hey…that’s me!

This brings up another peripheral study that was presented at ASH. A researcher studied the relationship of the “protective” effects of having the IGVH mutation against the very deleterious effects of having the p53 deletion/mutation (I have both). They found that if you have the p53 deletion, having the IGVH mutation doesn’t seem to confer any protection, the deadly effects of the p53 deletion being the dominant factor. Too bad for folks like me.

Another study of ibrutinib which bears reading and studying is one presented by Dr. Susan O’Brien, also from M. D. Anderson. You can see her paper here:

https://ash.confex.com/ash/2013/webprogram/Paper61648.html

In Dr. O’Brien’s paper, they have apparently combined the results from the Phase 1 study of ibrutinib, which had 108 patients in it, with the forty of us in the Phase 2 study, to give a total of 148 patients. She breaks the data down according to whether the patients had previous treatments and had relapsed or were refractory to treatment (RR) or whether they were getting their first treatments, being “treatment naïve” (TN). She further breaks the data down into the patients’ ages, number of previous therapies, time on the drug and more.

They have found that the serious adverse events decline after the first year and that most patients tolerated the drug pretty well. After about two years on the drug, 25 of 31 TN patients were still taking it and only one had shown disease progression, with no deaths noted. On the other hand, of the relapsed patients (RR), only 68 of 117 (58%) were still on the drug and 21 had noted disease progression. Notably, there have been 11 deaths in this RR group of 117 patients. However, the drug shows great promise, as the overall response rate was about 88% for the whole group, with most patients showing a partial response or better. She noted that after more than two years (average 27 months) on the drug, of those patients who had achieved at least a partial response, the median duration of response (DOR--the average time it takes patients to fail on a drug) had not been reached and could not be calculated as 76% of the patients were still alive without disease progression. That’s an amazing statistic. And a very hopeful one. I suggest you take a look at her abstract if you’re on this drug or considering taking it.

One last abstract I’d like to mention is one relating to the upcoming therapy called the Chimeric Antigen Receptor (CAR) procedure which is very exciting and is being studied in many places. It may be able to be a cure for many malignancies and is being studied mostly for leukemias at this point. It enlists the patient’s own immune system to seek out and kill the diseased cells. I won’t describe it here, as I’ve mentioned it previously and much more about it can be found elsewhere on the internet.

This procedure was pioneered by Dr. Carl June’s folks at the University of Pennsylvania. His early study of three patients resulted in two of them apparently being cured of CLL, though they remain immune deficient. In any case, it is interesting to see what percentage of the study patients are responding to therapy. This abstract also comes from Dr. June’s group. You can see his ASH abstract here:

https://ash.confex.com/ash/2013/webprogram/Paper58607.html

This shows that, although the procedure has some excellent results, it doesn’t always work. Of 24 CLL patients who underwent CARs therapy recently, only 5 had complete responses, 7 had partial responses and 12 had no response. The results were a bit better for pediatric patients with ALL. Of 14 patients, 8 had ongoing complete responses and four have relapsed. However, it needs to be remembered that all these patients were desperately ill and essentially had no other options. My point, though, is that for all the excitement surrounding CARs, this procedure is in its early stages and is not a cure for all who enter into these studies, with possible complications, deaths, relapses and such. But, it still holds great promise for the future.

I’m still doing quite well and will be going back to Houston for another check-up and bone marrow biopsy in about six more weeks. Meanwhile the blood counts I have been getting monthly here in Denton are remaining pretty much normal. Hopefully I can give you another good report next month.

Dave

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.

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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.

Dave

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.”

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!

Dave

www.adventureswithleukemia.blogspot.com

“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.”