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.

**************************************************************************************************

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.”

Lucky Man

Dave’s Great Adventure

Book 5, Chapter 2, Verse 3

Yes, I am a lucky man. Very lucky.

"Richard Fortey [author of LIFE: A Natural History of the First Four Billion Years of Life on Earth] has always found it amusing that centenarians, asked why they've survived so long, tend to credit their habits. The secret to longevity, they'll tell the local newspaper, is a glass of whiskey every day, or hard work and crossword puzzles. None ever ventures that it's a matter of genes and luck."--from The Wall Street Journal

All of us are lucky. The fact that we’re writing or reading these words is, by itself, an indicator of how lucky I think we are because there are so many aspects of life over which we have absolutely no control. We haven’t been on a plane that went down over the Atlantic. Nor have we been in a fatal auto accident. We weren’t in the World Trade Center on 9/11 or in either of the aircraft which were murderously crashed into them. We haven’t contracted a fatal infection. None of us has been murdered in a drive-by, a mugging or a home invasion. In fact, things that happened before we even “were” show our luck, as just enough of our dad’s sperm reached our mom’s ovum, at just the right time of the month, to allow one lucky little tadpole to fertilize it. Then, the fertilized ovum somehow found its way through the maze of our mom’s female plumbing and into the uterus. Many just get lost. And then we implanted in the uterus and grew. Only about half of the fertilized eggs actually survive. We did. We were lucky. We had no control over this process but, for us, it worked just fine.

“Yew arre varry locky to live in U.S.,” said Dr. Strati. Dr. Strati is an Italian physician, a “fellow,” who is working at M. D. Anderson, learning the sub-specialty of oncology and the management of leukemias. We had been discussing my 17p deletion/p53 mutation which we had discovered just over a year before. That mutation made my disease much more difficult to treat and reduced my life expectancy, in the absence of a successful stem cell transplant, to about a year or two. It makes the disease so difficult to treat that in some places, like Italy, apparently, I wouldn’t have been treated at all, or at least wouldn’t have been expected to survive very long.

I was immediately reminded of a patient from Germany whom I had been told about by Dr. Keating, a patient who had come to M. D. Anderson with advanced CLL, even worse than my situation. Her white count had been 300,000, she had a hugely enlarged spleen, low platelets and many other dismal prognostic features. She was in her late 60s, and her situation was so dire that she was not going to be treated in Germany, where, in the semi-socialized medical system they have, your treatment depends on your expected outcome and the years of survival that might be anticipated as a result of your treatments. This patient, said Dr. Keating, was in the “no go” category in Germany, as she was too old and her expected longevity was too short for her to qualify for therapy. So, she had come to Houston and to Dr. Keating looking for help, where she was included in the Phase I part of the PCI 32765/ibrutinib study in late 2010. And, as sick as she was, she has since done extremely well on this wonderful new drug.

My luck however, began about a decade before. I found I had chronic lymphocytic leukemia (CLL) in early 2002 and at that point I was just certain I had only five or six years to live. After all, my father had this disease and lasted just five years with it. And there were no good treatments available. Yes, there were many, many treatments available, and many of them could induce at least a partial remission but as a rule, the disease almost invariably came back and the patient still died within five or six years, treated or not. That led to a school of thought that it wasn’t worth doing the treatments at all. There was a lot of “watch and wait” going on. Or, as we patients called it, “watch and worry.”

But, within months of my diagnosis, while my doctor and I were casting about, trying to figure out what we should do or not do with all the unsatisfying options available, a paper was published from the researchers at M. D. Anderson describing a new three-drug combination that they had tried experimentally on about 200 patients. It included a drug not even approved for CLL, a drug called Rituxan (rituximab) and two other standard CLL drugs, Fludara and Cytoxan. The results were incredible. They had achieved 80% or so remission rates, and this was in a time a 30-40% remission rate with other drug combinations was considered to be very good. This new combination was called FCR, for the initials of the three drugs and it soon became the “gold standard” in the initial treatment of CLL. That article led to my first bit of luck.

The lead investigator was a doctor named Michael Keating, and I was intrigued by his involvement in this study, so I began reading other articles and studies in which he had been involved. I quickly learned that he was a power within the CLL community and was involved in many, many studies of drugs designed to fight or even hopefully cure the disease. I saw his name everywhere; on articles on-line, as a speaker at scientific meetings, in interviews I could watch on-line and so on. This guy, I figured, is one of THE experts in the world regarding CLL. I need to follow what he’s doing.

Anyway, we used Dr. Keating’s FCR stuff in 2002 in Denver, and it put me into an absolutely complete remission. A couple of years later, when the leukemia was coming back we used another combination including the Rituxan to put me into remission again. Shortly thereafter we left the Denver area and moved to Texas, to be closer to our family (because I figured I’d be dying by 2006 or 2007 or so). And about this time the disease recurred yet again. I knew it would; after all, by definition, my disease is incurable.

In late 2007 I was needing treatment again and my doc in Denton was rather out of ideas. There were no great options for treating patients who needed a third round of therapy for CLL. He suggested sending me to M. D. Anderson to see what they might recommend for someone like me. He asked who I’d like to see down there. Now, I was surprised to be asked who I wanted to see, figuring that I’d be assigned to whomever they wanted to send me to, some resident or fellow who happened to be on rotation there. But, having been asked the question, I said, “Dr. Keating?” in a plaintive, hesitant way, as I figured that there was no way at all I’d be able to get in with a doctor of his stature and prominence. I thought that would be like asking Steve Jobs to come over to fix my Mac computer.

But, amazingly, I did get an appointment with Dr. Keating, which led to six months of experimental chemotherapy, putting me back into a three year remission. And when that finally failed last year, it led to another experimental trial of a new drug. But by then, I had the p53 mutation and, really, nothing was going to work very well.

That’s where I was last February when my most recent chemo failed. I had been through four different courses of chemotherapy over ten years and was left with no good options besides that of a stem cell transplant, which could be potentially curative but also could be a lethal choice. About 15-25% of folks getting stem cell transplants of the kind I’d be needing die of the procedure or its complications. I had met with the kind folks in the M. D. Anderson transplant clinic to start setting up such a procedure when my previous bits of luck led to my most recent lucky streak.

The day after meeting with the transplant coordinators I met again with Dr. Keating. He had said he’d try to get me into a new drug trial that was about to open and he did! He was able to get me into the newly available PCI 32765/Rituxan drug trial, a study including only forty lucky souls and the one which I’ve now been in for five months. It has so far allowed me to avoid a stem cell transplant and allowed me to live an almost entirely normal life.

So, my luck started when my doc in Denver, in 2002, read an article authored by Dr. Keating which led to my getting the FCR treatment that year and led me to start inquiring about Dr. Keating’s CLL studies. That led me to ask to be seen by him when I went to M. D. Anderson in 2007 and that led to my ultimately being lucky enough to be one of only forty pretty sick patients to be selected into this near-miraculous drug study.

And the results continue to be astounding. I went back to Houston in June and had another round of tests, including a bone marrow biopsy, CT scan, chest x-ray, and blood tests. The results are spectacular. The bone marrow biopsy shows that, pre-treatment, 69% of my marrow cells were leukemic but after just three months on the drug, that number has been reduced to 23%. Similarly, pre-treatment I had numerous grossly enlarged lymph nodes, up to the 16cm. mass (about seven inches wide) I mentioned in my last message. After the three months of therapy, all my tumors have been reduced to about 12% of their previous size by volume (they have been reduced by about 50% in all dimensions). The blood tests show continued dropping of my white cell counts and stable red cell and platelet counts.

But not only has my disease been considerably diminished already by just a few months of therapy, but during this time I also have found that my chronically swollen, painful and frequently infected sinuses have healed and have not been a problem in months; warts on my hands, which I have been battling for ten or twelve years have almost entirely disappeared; a chronic cough and frequent wheezing I’ve had for a couple of years has cleared up; and my hair, which has always been very fine and straight is getting increasingly coarser and is starting to curl!

The other side effects continue to be a nuisance but are tolerable. I’m still having intermittent joint pains in my hands, feet, ankles and wrists. But the pains, when they appear, last just four or five days at a time and then go away for a few days, before moving on to some other joint area. I can generally take some anti-inflammatory drugs and go on with my life. Additionally I’ve been having muscle cramps, spasms and twitches fairly regularly. I have been taking magnesium supplements in several forms to combat these symptoms but the folks in Houston told me to try tonic water. Yeah, tonic water! Tonic water contains quinine which is a long-time remedy for leg cramps and restless legs. So, I drink a couple of cans a day and take a little magnesium in the form of a Maalox antacid and I do pretty well. Sure beats dealing with the complications of a stem cell transplant.

Here’s another example of how lucky I think I am to be in this study. In the first phase of the PCI 32765 study, it was known, or at least assumed, that the drug might be a good lifetime treatment for CLL, but was unlikely to be a cure. Since it wasn’t to be a cure, two of the original participants dropped out of the study and opted for stem cell transplants. One of them has since died of the transplant. I haven’t had to face that decision yet, thanks to the fantastic results of the PCI 32765.

Now, these are still very short term results, as I’ve only been on this drug for five months, but most of the folks who started the Phase I study back in October 2010 are still on the drug and at this point, many of them have been on the drug almost two years, and still no serious adverse effects have been noted. Amazing.

Yes, I am so fortunate to live in the U.S. If I had been born in Uganda, Peru, China, Russia or perhaps even England or Germany or dozens and dozens of other countries across the world, I’d either be dead or dying by now. And of course, I had no control whatever over where I was born. It just happened that way. I’m a lucky man. I’m being watched over by Someone. I don’t know what I’ve done to deserve this Gift, but I’m eternally grateful and hope to live my life in a way which justifies what I’ve been given.

I’m going back to M. D. Anderson next week for the last of my monthly infusions of Rituxan. After that, I’ll be solely on the PCI32765/ibrutinib, probably indefinitely as long as it’s continuing to work. We’ll be getting periodic bone marrow biopsies, CT scans and blood work, but our lives will no longer be so rigidly planned around our monthly trips to Houston. More later.

Dave

[--Over lunch a couple of days ago, Mike and I were talking about how lucky we were. We both have lethal diseases. He has lung cancer which has spread beyond his lungs and I have an incurable leukemia. There are no cures for our diseases, but there are treatments and we’re both currently undergoing novel experimental therapies. But the reason we feel so lucky is not just our access to these experimental treatments, but it’s because we’ve both had good lives. We’re both Vietnam vets and both of us saw buddies and brothers in arms who came back from the war in a box with a flag draped over it. We came back intact and have been able to have another 45 years of productive lives with family and friends, 45 years our dead buddies didn’t get. And, we’ve been able to live quite a bit of time beyond the dates of our diagnoses, years that I count as “bonus” time, as you live your life differently when you’ve been told you have an incurable, deadly disease. You really do. Life feels different and different things are important to you. We’re lucky to have the opportunity to have all these extra years. And if we reach the point where there is nothing else to be done for our diseases and it’s our turn to check out and get into the box with the flag on it…well, it’s been a great ride.]

“Flower, don’t be proud of yourself. Eventually you will fade.” --Afghan poem.

Your Questions Answered

Dave’s Great Adventure
Book 5, Chapter 2, Verse 2

Over recent weeks and months, as I’ve gone through several rounds of testing and evaluation, I’ve been asked many questions about what’s going on and so I thought this would be a good time to answer them for all of you.

1) What ever happened to the bone marrow transplant or stem cell transplant you were getting ready for? ---When I developed the p53 mutation, which I discussed last summer, wherein I lost my tumor suppressor gene, it meant that I was going to have a markedly more difficult time with my disease. It meant that chemotherapy was unlikely to work very well anymore and that my survival was likely only going to be a couple of years or so. The only chance I had for long term survival would be to have had a stem cell/bone marrow transplant (the terms are interchangeable and mean the same thing) to replace my diseased bone marrow with healthy cells from a donor. We were getting ready for such a transplant earlier this year, just as I was also being evaluated for inclusion in the PCI 32765 study. When it appeared that I would be eligible for the study drug, the bone marrow transplant was put on hold while we waited to see how I responded to the drug. I’m still scheduled to see the stem cell transplant team in a couple of months, after I have another CT scan. We need to see if my tumors are resolving, which I’m sure they are, at least in the very short term. If I fail to respond to the drug in the future, we will still proceed with a transplant at some point. However, as long as I’m doing as well as I am now, I’ll be able to avoid this procedure.

By the way, I mentioned weeks ago that based on the preliminary HLA cell typing that had been done on me in 2002, when my siblings were being tested as possible cell donors for me, that there were already about 70 possible donors listed in various blood banks. That was based on, I believe, looking at 10 of the 12 HLA antigens (or markers) on my white cells. Now, after having completed the testing on all 12 antigens, that number has been reduced to about 36 possible donors, which is still incredible when you hear that only about 30% of folks who need stem cells ever find a match (and that’s why I would encourage all of you to consider going to a blood bank near you and getting tested by simply having your cheek swabbed. You could, quite literally, save someone’s life).

I also found out, generally, where these 36 donors are. It turns out that most of them are in North America, one is in England, a few are in Germany and, get this, two are in Japan. Japan! I’m dumbfounded to find that I have potentially matching donors in Japan. And I’m also surprised to find that none of my potential donors are from Sweden since, as I mentioned, genetically I’m half Swede. I fully expected to find a cluster of donors from southern Sweden where my dad’s parents came from. I wonder if perhaps the Swedes don’t share their blood bank data with other nations or something.

2) You said you had numerous tumors in your abdomen and had a PET scan to look for cancerous lesions, but then you said the PET scan was negative. How can that be?

---Well, the PET scan indeed looks for malignant tumors and I indeed had numerous, as in “dozens and dozens,” of tumors in my chest, belly and pelvis but the PET scan was negative because my leukemia cells, which were clogging up my lymph nodes, really aren’t cancerous. Yes, I have a blood cancer, leukemia, but the individual cells that I make way too many of, and which live way too long, aren’t really cancerous. They just live for an indefinite time and lodge in my bone marrow and lymph nodes, taking up space so that eventually there is no room for the normal cells to live and reproduce. At that point a person with CLL will become anemic and unable to fight off infections and death ensues. But the leukemia cells themselves are not the malignant kind of cells which spread throughout the body and invade other organs like malignant cells from prostate cancer or breast cancer.

3) But since you had a huge tumor in your pelvis (you said it was 16 centimeters in size) and since the PET scan, though negative, isn’t as definite as a tissue biopsy, why did you cancel the fine needle biopsy that was being scheduled for you?

---Yes, I had many tumors in my belly, among them the aforementioned 16 cm. tumor, which I could feel when I lay on my stomach to have my bone marrow biopsy. It felt as if I was lying on a softball. And, yes, a tissue biopsy is certainly more definite in terms of diagnosing cancers than a PET scan, I suppose, but in the case of using the PET scan to rule out Richter’s Transformation (a seriously malignant transformation of CLL) we decided that the PET scan was good enough. A biopsy could only confuse the issue of whether or not I could enter the study. We had evidence that I was free of lymphoma, by the PET scan, and decided to go with that. If we had done the biopsy, then the pathologist reading the tissue specimen would have been looking at dozens, or hundreds, of little Rorschach tests, as he or she decided whether any of them looked malignant. If they found a few they couldn’t be sure of, it might have kicked me out of the study or delayed my starting the study drug. If, on the other hand, it turned out that I indeed did have an undiagnosed lymphoma, the worst that would happen is that I would have failed the study drug, the PCI 32765, and would have gone on to intensive chemotherapy and a stem cell transplant anyway.

4) Why did they almost keep you out of the drug study just because you had used the Rituxan three times in the past?

---I’m actually not quite sure about the answer to this, but I have some thoughts. First, in the initial studies of the PCI 32765, they used the study drug by itself, and got very good results. In the new study, of which I am a part, they are now combining the PCI 32765 with intermittent Rituxan; weekly at first, then monthly for up to six months (remember that Rituxan is an antibody which attacks a protein on the surface of CLL cells, destroying them). The theory is that the PCI 32765 will drive the CLL leukemia cells out of my bone marrow and lymph nodes and then the Rituxan will be in my bloodstream to directly kill them. I think possibly the reason for the restriction on prior exposures to Rituxan which were made in this study was because the Rituxan is a mouse-based antibody. Being at least partially of non-human origins, and having some non-human proteins, patients can actually start producing antibodies against the Rituxan itself; antibodies against the antibodies, if you will. That would reduce the effectiveness of the drug and could also lead to more side effects. But, if that reason is correct, then I wonder why my exposure to the Arzerra was also included in the count of prior uses of Rituxan since Arzerra, like Rituxan, is also an antibody against CLL cells but is “humanized,” and so I wouldn’t think it would induce antibody exposure to Rituxan. But perhaps the two drugs are more similar than I realize and perhaps an antibody against one might affect the other as well. I have recently found that yet another similar antibody drug has been developed and has been called “fully humanized,” so perhaps the Arzerra is not as “human-like” as I thought.

5) If the drug is working so fantastically well for you, why are there only forty people taking the drug in this study? Why don’t they give the drug to all the patients with CLL?

---There are two parts to this answer. First, though the drug seems to be working incredibly well on me (and the other folks in the study, too, from what I’ve informally heard) it is a very new drug and there are absolutely no long term studies of it. The folks who have taken it the longest started on it in, I believe, October 2010, so there is only 18 months of data on the drug, in a very small number of patients (the first study of the drug started with about 117 patients, all of whom were pretty sick, as is generally the case when a Phase I study is started with a new drug that has not been used on humans before). So, though it looks like the PCI 32765 works very well and that there are no serious side effects known yet, it could be that down the road a bit, say in two or three years or more, some serious conditions could develop. I’m hoping that two or three years from now, all the folks on this drug are still doing just fine, but it might turn out that we all start getting diabetes or brain tumors or something. Additionally, the PCI 32765 works on the “Bruton’s tyrosine kinase” ( description to follow) which is present not only in all CLL cells but on ALL NORMAL B lymphocytes, too. It can in theory and perhaps in practice too, cause very low antibody counts in folks taking it after some length of time, by killing off too many B lymphocytes, which make your antibodies. Hopefully we won’t all be getting sick after using the stuff, but we don’t know yet. As more data is collected on the drug’s use, and if it seems to be generally safe in the longer term, it will be used in a more widespread manner. The second part of the answer is that, though there are only forty patients in “my” study, the Rituxan and PCI 32765 combination, I believe that M. D. Anderson and other research facilities are doing several different studies with the new drug, in combinations with other anti-CLL drugs, like Revlimid, FCR and other combinations. Plus, the National Institutes of Health, on the east coast, is also doing a study of about another 100 folks. So, a few hundred folks are actually getting the drug right now, but hopefully it will soon be shown to be safe for widespread use throughout the world.

6) So, really, what is this new drug?

--First, I want to tell you that this new stuff, the PCI 32765, has acquired a name which is much easier to deal with that the string of numbers and letters I’ve been using. I have seen it called “ibrutinib” in the last couple of months. The PCI 32765 designation was probably the manufacturer’s in-house development code and the “ibrutinib” seems likely to be its generic name. I’m sure the company will come up with some snazzy, cute name for the drug soon; something like “CeLL-Out,” “CeLL-cide” or something. It’s one of several new drugs being tested which are an entirely new class of drugs in the battle against CLL, a class called kinase inhibitors. They all have strange names thus far. Another blogger named Dave, who writes the excellent “CLL Diary,” calls them the “license plate drugs” as they have names like CAL 101, ABT199, AVL 292, SGI 1776 and my own PCI 32765. I mentioned this stuff in passing a couple of months ago when I was speculating on just what new study I might get into. You may remember that I talked briefly about the PCI 32765 as the “BTK” drug, which name reminded me of the “bind, torture, kill” serial murderer in Wichita, Kansas many years ago. The “btk” drug actually is a “Bruton’s tyrosine kinase inhibitor,” a name only a biochemist could love. Now, I know that both PCI 32765 and the term “Bruton’s tyrosine kinase inhibitor” mean nothing to anyone out there, so I’m going to paste in a simplified explanation which appears in the wonderful CLL information web site, “CLL Topics,” by Chaya Venkat, whose husband died of CLL in 2008. This will get a bit long, but it’s so well written I encourage you to dig into it. Here is her explanation of what “kinases” are and how they work in leukemia, CLL specifically. I have edited her description very slightly.

“Kinases – master controllers:

Kinases are extremely important enzymes that control much of how the cells in our body function. There are several hundred different kinases, controlling different functions. One type of kinases, called protein kinases, is the largest group. Protein kinases can transfer a phosphate group from ATP to a protein in a cell, thereby activating the protein.

If that bit of chemistry began glazing over your eyes, try this for size. Kinases function as an “on” or “off” switch. Without the help of a particular kinase turning the protein “on”, the protein in question is inactive and cannot do the job it is supposed to do. Thus, kinases control much of the machinery of the cell – its ability to proliferate (reproduce), move about the body, ability to receive or send messages to its neighbors, whether it lives or dies. To put it in blunt terms, kinases are the central master switches of how each cell in our body works. As you can imagine, all hell breaks loose if one of the master switches goes awry, if it gets stuck in the “ON” position too long for example. Mutations, deletions or mangling of the structure of a regulatory kinase can play havoc with the particular protein and the cell function it is supposed to control. Most if not all human cancers are thought to be caused by one or more malfunctioning kinases.

Kinases make nice targets for new drug development:

So, if a malfunctioning kinase is at the root of a particular cancer, how about blocking that kinase and thereby block its bad influence on the proteins it is supposed to control? Great idea, but not that easy to do in real terms. Many kinases share common features. So, a drug that is developed to block a particular kinase may also block a bunch of other perfectly normal kinases, and thereby disrupt some vital function of the body. Broad spectrum kinase inhibitors can be very toxic because they can block too many vital pathways – a case of the cure being worse than the disease.

Even Gleevec, the miracle kinase inhibitor drug for CML, has some toxicity concerns. A 2006 article linked Gleevec to heart failure in a small percentage of patients. ”Ten CML patients treated with Gleevec at the M.D. Anderson Cancer Center in Houston developed congestive heart failure, although they had normal heart function when they began taking the drug. Studies in mice and in culture showed that the Abl tyrosine kinase protects cardiac cells from damage; when it is inhibited, heart cells die.” This was a bit of an “unanticipated side effect”, according to the researchers.

I am pointing this out not to take away anything from the game changing ability of Gleevec. It has truly been a miracle drug that paved the way for better and more targeted drugs in its wake. But all too many times I get letters from our members upset with the slow pace of clinical trials, unable to see the point of all these careful protocols and detailed research. Why can’t the FDA just approve CAL-101, and get done with it? After all, it is a biologic drug and not a nasty chemotherapy drug, it can’t possibly hurt – can it? The answer is YES, IT CAN. Biologic drugs can hurt, can even kill. This is one of the reasons why early stage studies (Phase I trials) generally recruit late stage, sicker patients, people who have been through several layers of therapy already, so called “salvage-cases” with few good choices left. ”Do no harm” is a very important oath to remember, if you are a clinical researcher and you wish to avoid unnecessary tragedies. Do we have similar kinase targets in CLL?

Turns out, we do. Not just one target, but four of them. They are not just the BTK kinase we're mentioned, but kinases called SYK, Pim K, and Pl3-Delta. And all four kinase targets are being examined, with suitable small molecule inhibitors that may be able to stop them cold.

Unlike CML, which has one particular messed-up protein (as you would expect, the protein controlled by Bcr-Abl kinase is called Bcr-ABL protein) that is responsible for the cancer, CLL does not have any one single such protein. But in the last few years we have learned a great deal about what makes CLL tick. We know for example, that much of the survival advantage of CLL cells lies in their ability to resist suicide signals from the rest of the body. This ability to ‘live long and prosper’ is hugely enhanced when the CLL cells are surrounded by their closest friends and relatives, so called “nurse-like cells” in their immediate microenvironment, constantly giving them encouraging feedback. We know by now that just about any therapy can bring down CLL counts in the blood. Shrinking swollen nodes and clearing infiltrated bone marrow – that is a lot harder. This is because out in the open blood circulation CLL cells are not all that hard to kill. But once they are nicely tucked away in the bone marrow, swollen lymph nodes, spleen, liver etc, they are much harder to kill.

The four kinases listed above are known to be over abundant in CLL cells, cooperating with the microenvironment. They magnify the survival and proliferation and maturation signals the CLL cells receive from their neighboring nurse-like cells, through the B-cell receptors that each B-cell has on its surface. If we can take away this constant and soothing pep-talk magnified by overactive kinases listed above, it becomes a lot easier to kill the CLL cells.

This is a distinctly different approach to killing CLL cells than the usual chemotherapy drugs we have come to love and admire (Not!). We are not trying to poison the CLL cells, we are only trying to kick their damn legs out from under them. And when they are down and floundering around out in the open, if they are not already dead because of their scary isolation from their fan club, that is when we can kill them easily with appropriate therapy. For a change we have an embarrassment of riches, four different kinase targets to try and block. The BTK (Bruton Tyrosine Kinase) and PI3K kinase are in the lead. The small molecule drugs that we hope will block these two kinases respectively are PCI-32765/ibrutinib and CAL-101.” --Chaya Venkat, CLLTopics.org

By the way, the Bruton’s tyrosine kinase gets its name from Dr. Ogden Bruton, an Army doctor at Walter Reed Army Hospital back in the 1950s, who described a profound immune deficiency with very low lymphocyte counts in certain of his male patients. This condition turned out to be X-linked, in other words, linked to the X chromosome the male child had inherited from his mother. Fifty years later the defect was found to be in the tyrosine kinase of the children’s B lymphocytes. That discovery made the tyrosine kinase a tempting target for research into treating B lymphocyte malignancies, like CLL. Finally a way to block the kinase has been developed!

7) How are you doing on this drug so far?

--In the short term (two months) I am doing just great. The lymph nodes we could feel, as well as those in my belly, seem to have completely melted away. In fact, during the first month on the PCI 32765/ibrutinib, as the tumors were disappearing, I lost about ten pounds! Of course, I then took the opportunity to eat more Mexican food, pizza and desserts, so I’ve gained back about half of that as I haven’t been watching my diet as closely as I should. I am having no nausea, no hair loss, no loss of appetite, and no peripheral neuropathies, as some chemotherapies can cause. I do have weird, transient, migratory joint pains, primarily in the small joints of my hands and feet, but also some significant pains in my low back, knees and ankles. They are sometimes fairly painful, like small attacks of gout or something (though I am taking allopurinol to avoid such things). But those joint pains seem to be the worst of my side effects. I am beginning to feel more energy, and I have noticed far less sinus congestion and have had no sinus infections since starting the new drugs (I was having to be treated for sinus infections on a regular basis before beginning the PCI 32765/ibrutinib and Rituxan).

We are going back to M. D. Anderson this week where I’ll get the third of my six monthly infusions of Rituxan and at the same time we’ll be getting a panel of lab tests, to see how my white cell, red blood cell and platelet counts are doing. I’ll be getting another CT scan in June to see how much is left of my many enlarged lymph nodes. And, so, we’ll see how things go!

Dave

www.adventureswithleukemia.blogspot.com

“We must be willing to let go of the life we have planned so as to have the life that is waiting for us." -E.M. Forster (as quoted by David Arenson in his CLL Diary; www.clldiary.blogspot.com )