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 )

The Magic Stuff Called PCI 32765

Dave’s Great Adventure
Book 5, Chapter 2, Verse 1
April 26, 2012


“…there I was, under a sheet, naked except for some surgical scrubs they’d given me, but with the pants down around my knees….”

THE WAIT
On Leap Day, 2012, February 29th, I was given the news that I had been accepted into the clinical trial of the new oral agent for combating chronic lymphocytic leukemia, the so-far unnamed drug that goes by the clumsy label of PCI 32765, the manufacturer’s in-house development code, I presume. I instantly assumed we’d be starting the study right away because just a couple of days before, during the fifteen minutes between being told I was in the study and being then told that I was excluded, Dr. Keating’s staff had been frantically trying to arrange the things I would need before I could begin taking the new drug, such as a bone marrow biopsy, an infusion of Rituxan and more. I was thinking we’d have to go back to the hotel to extend our stay.

But, almost as soon as I was told that I was in the study, I was told that we’d start the protocol, oh, maybe in the middle of April. What! It appeared that when I had briefly been excluded from the new study two days previously, I’d lost my place in line, as it were. I asked if we couldn’t start any sooner, as I was extremely anxious to get started for many reasons. Gracy looked at her schedule and said it was filling rapidly but maybe we could start on March 27th, four weeks away. I asked if she would book me into that slot as it sounded a bit better than sometime in April, which sounded years away to me.

We left Houston with that date in mind, and were very thankful to be in the study, but I was apprehensive about waiting four weeks to start. The new drug was just about the only thing standing between me and a bone marrow/stem cell transplant, with all its possible risks and complications, including, at a minimum, a 5-10% risk of dying, according to Dr. Khouri. I was fearful that something would happen to again get me excluded from the study; I’d get sick with pneumonia, I’d be injured in a car wreck, I’d fall and break a hip, I’d have a heart attack, or any of the myriad things that can normally happen to a 65 year old guy. I really wanted to get the study started and I wanted to make sure that I stayed healthy during the intervening four weeks. But I didn’t want to become a recluse.

Months before, probably last Fall, we had planned a trip to Moab, Utah, to be with the Leukemia and Lymphoma Society’s Team In Training (TNT) for a half marathon that is run there every March. A group of TNTers from Colorado, including some good friends, was going to be running in the event and I’d been invited to speak at the dinner which is held the night before the event. Generally a survivor of lymphoma or leukemia speaks to the runners, who by then have spent months training for the event and raising money for research and patient assistance. We survivors want to let them know how much what they’ve done means to us. But for many months I hadn’t been sure if I could keep this commitment, as I’d been undergoing treatments with the Arzerra all Fall and then found that my lymph nodes were swelling massively in February. But, when we found that I wouldn’t start the new therapy until late March, it appeared that I would be free to attend.

I had some reservations. Generally Kathy and I try to avoid crowds and folks who are obviously sick with coughs and colds, and we’re obsessive about hand cleaning, avoiding shaking hands, touching doorknobs and such. Going to the event would mean doing precisely what we usually try to avoid. We’d be traveling on crowded airliners, sitting in airports and sitting near lots of strangers in shuttles. At the marathon event I’d be among crowds of people, shaking lots of hands and hugging lots of folks. But, I really wanted to do it. I’ve been a part of TNT for five years now and they are just routinely wonderful people. I wanted to be with them and to be able to tell them my story. So we went. Everything went well and we had a great time with our teammates in Moab. And I didn’t catch a cold, either.

But during that month wait, I could feel the masses in my neck and under my arms getting bigger every week, and my belly was getting more and more distended as the previously discovered tumors kept growing. Only later was I to find out how much they had grown. All I knew was that it was getting harder to breathe and that I couldn’t eat very much. There just wasn’t room in my stomach and chest. And the “marbles” in my armpits grew into “golf balls.”

THE PREPARATION
Before and after our trip to Moab, Kathy and I were planning out our next month. We knew the study would include many weekly trips to Houston, at least initially. That wouldn’t leave a lot of time for domestic tasks, so were setting up lawn care, paying bills and asking our neighbors to get our mail and papers and such. And then we left for Houston, to start the new drug regimen.

But there were still a few hoops I had to jump through. Our first day there, on the previously appointed March 27th, I had labs and tests scheduled virtually all day, from early morning until my last appointment, a CT scan, scheduled from 7PM to 10PM. That was to prove to be the most entertaining of my evaluations. But I’ll get back to that.

I had multiple tubes of blood drawn first, before seeing Dr. Keating and his nurse Jackie. They did a physical exam on me and noted the sizes of my palpable masses. The tumors under my arms were now about golf ball sized and the ones in my neck had grown to about marble sized. Then I had an EKG scheduled, to ensure that I had no significant heart irregularities (besides my long-standing irregular heart beat and my floppy mitral valve). I was able to get my EKG done very early, in the morning rather than the 3PM it had been scheduled, so we thought that perhaps we could get my bone marrow biopsy, scheduled for 4:30PM, done early as well if we checked in early. We were hoping to get a bit of a rest in the afternoon before we went for the CT scan at 7PM, since it promised to last until late. And since I was instructed not to eat anything for three hours before the CT, we wanted to have a break between the bone marrow biopsy and dinner time so I could eat before the three hour limitation started.

We checked into the bone marrow biopsy clinic at 1PM. I told the receptionist that I was very early, but hoped that I might be able to get in before the scheduled time. She let on that, yes, there was in fact a good chance I’d get in early. So Kathy and I found a seat, away from most of the other patients, like we always do, and we waited. And we waited. And we waited. 2PM came, 3PM came, 4PM came and went and I hadn’t been called back. So much for getting in early. We killed the time with our smart phones, playing “Words With Friends” and “Draw Something” with our kids, long-distance. I think they were supposed to be working, but instead, they were entertaining us. But it really did help to pass the time. Finally, I was called back at 4:30.

Now, a bone marrow biopsy is probably one of the most feared tests a person can be told they need. I’ve seen folks weeping almost hysterically in the biopsy waiting area, so frightened are they. People like to tell others about just how excruciatingly painful it is. And, in fact, a bone marrow biopsy can be painful, but it doesn’t have to be. I’ll tell you that if any of you out there ever have to have a bone marrow biopsy, go to Houston and get it done at M. D. Anderson. Some places it’s so painful they give powerful IV drugs to help block the pain, but at MDA, you’re wide awake and totally conscious. There, they operate much like your dentist does. They use lots of local anesthetic and they wait a while to make sure it’s working before they bore into your hip bone to drill for marrow. The process, though not completely painless, is probably less painful that your average flu shot or falling down and spraining your ankle. And, the biopsies are done not by doctors either, but by trained nurses and PAs who do dozens of them every day. And they’re very good at what they do.

So, I ultimately finished with the biopsy but by then it was 5:30. We now had only thirty minutes to find a place to find dinner before I was forbidden to eat, in preparation for the CT scan. We quickly headed towards the Mays Building which is at least a quarter of a mile away, where the CT scan was to be done. It’s so far away that they have a golf cart shuttle system to take patients and staff to and from M. D. Anderson’s main building to the Mays Building via sky bridges. We had been there before and knew they had several snack bars so we headed for one. But, on arriving there we found that the building looked almost completely shut down for the night and all the snack bars had closed. So we backtracked a few hundred yards to the Rotary House International Hotel, which is also attached to MDA by sky bridges. We knew they had restaurants which operated during the evening hours and we were able to get in there and get me fed before my 6PM cutoff time for eating.

THE CT SCAN
After hurriedly finishing off my nutritious meal of fish and chips before 6 PM, we started walking back the couple hundred yards to the Mays Building. As we had noted, the whole building seemed to be pretty much shut down for the night. Most lights were turned down, desks were empty of receptionists and very few folks were anywhere to be seen except for an occasional security guard making his rounds. I allowed myself to think that with so few folks around we might actually get into the CT clinic early and be done before the appointed 9-10PM.

So you can imagine our surprise when we got up to the 7th floor CT clinic and walked into what looked like the midway at the carnival. It was brightly lit with perhaps 75 people milling about in the waiting area, sleeping on chairs, covered with blankets, reading, listening to their Ipods, and so on. A scrolling informational sign conveyed bad news: “One Unit Down For Maintenance, Expect Delays,” it said. Just like you see along the highway during construction.

I checked in for what was to be a long wait. I knew I had to “prep” for the scan, but previously that meant only drinking about a quart or so of salty-sweet “contrast” and then waiting about ninety minutes. But this prep was to be a bit more complicated. First I was instructed to drink about a pint and a half of a thick, viscous barium “fruit smoothie” within about fifteen minutes. Very chalky, and I got it down as fast as I could. It was tolerable. Then, a half hour later they called me back to put an IV in my arm. I was to have some IV contrast injected during the test as well. And, they told me, I was to have some “rectal contrast” too. “Uh, what?” “Yes, you’re getting rectal contrast too. Sign here to acknowledge that you’ve been told.” I signed as instructed.

Then we waited and waited. Folks were going back from time to time but the place wasn’t clearing out very fast. Finally, at about 10PM I was called back to the exam rooms. I was told to undress completely, underwear, socks, everything, and put on some hospital scrubs. Then I was given yet another bottle of “fruit smoothie” to drink and about 30 minutes later was taken into the CT room. They placed me on the table and covered me with a sheet. The nurse said, “Pull your pants down and turn on your left side.” I knew what was coming, and with that, yikes, she inserted a nozzle into my nether aperture!

So, there I was, under a sheet, IV in my left arm, my belly heavy with barium "smoothies," and naked except for the surgical scrubs they’d given me, but with the pants down around my knees and a tube stuck up my butt. I smiled, a wry smile. “This,” I thought, “is probably like what I put my patients though for so many years.”

The CT went quickly after all the waiting and we were glad to get out of there. But by now it was 11PM and the building really was shut down. We had to have security let us out and direct us to a shuttle to take us to the parking garage, about a half mile away, so we could get back to our hotel.

But, I had finally jumped through all the hoops, I could start the study. The next day I had my first dose of Rituxan which I had to have in me before starting the PCI 32765. I had a bit of a reaction to the anti-CLL antibody drug, as it was blowing up billions of CLL cells all at the same time so I needed some steroids, antihistamines and some Demerol to stop the shaking chills I was having. But, other than that it went well.

The PCI 32765
Astounding…just astounding.
The day after the Rituxan infusion I saw Dr. Keating and Jackie one more time. Things were looking great, though I did find that the CT scan showed that the largest tumor in my belly, which had been 8 cms.(about the size of an orange) in February, was now 16x8 cms. in size, about the size of a squashed cantaloupe, so fast was it growing. They cleared me to start the PCI 32765!

I had been given bottles of the drug a couple of days before and had immediately broken open the seal on the bottle to see what this new wonder drug looked like. It was just a bunch of generic, grey capsules without any markings on them whatsoever. But now I was cleared to take it. I had supposed that since I was taking an experimental new drug for the first time they would want me to take the first dose while I was with them so they could watch me for a bit to see how I handled it, but they didn’t want me to stay at all. Instead, they said “Bye bye” and with that we were off, driving back to Denton. The instructions with the drug said I couldn’t take it until at least two hours after I’d eaten, and since I’d eaten breakfast, I couldn’t take the drug while we were in Houston. Instead, I ended up taking my first dose while driving up Interstate 45 at a speed somewhat faster than the posted 75 mph limit. It was a good omen.

I’ve now been on the PCI 32765 for four weeks, and it has worked astoundingly well and with astounding rapidity. I could feel a difference in my lymph nodes under my arms within days. Within ten days my belly was not so distended. And now, after four weeks on the stuff there are no longer any palpable masses in my armpits, neck or belly. I feel so absolutely fortunate to have been selected to be one of the 40 high-risk patients in this study. The results are unbelievable so far. Now, it’s only been a month so far, but other folks in the previous Phase I study have now been on the drug for up to 18 months or more and still no significant problems have developed. I expect more good things. I’ll “get” to have another CT scan in a couple of months to see how the 16 cm. mass in my belly is doing, but already I can tell from the fact that my abdomen is flat now, that it’s shrinking rapidly.

And that is enough for now. I have let this message get far too long so I’ll close and send more technical details of the drug, and answer your questions in another letter.

If you’ve actually read all this, I thank you for your patience with me.

Dave

“We also know that everyone gets their own box of challenges, they just come in different size boxes with different colored bows. We hope your box has been lost in the mail.”—from our friend Sarah, whose husband Mike is battling an incurable Stage 4 lung cancer. They’re going on a cruise to England and Scotland this summer.

“I’d rather die living than die dying.”—Steve Appleton, chief executive of Micron Technology (semiconductors) who recently died when his high-performance airplane crashed in Boise. (Mike and I agree with this philosophy.)

Great News!

Dave’s Great Adventure
Book 5, Chapter 1, Verse 5
March 1, 2012
Great News


I have great news from Houston tonight. Today Kathy and I found a wonderful little Mexican restaurant not too far from our hotel. We've been looking for places to eat since we got here and have found lots of neat little places but it's hard to find the kind of Mexican food we really like. But today we found a little taqueria not too far from here that has enchiladas with real red chile sauce and not chili con carne like most of the Tex-Mex places in Texas have. It's nice to know where great places to eat are.

In other absolutely wonderful news from Houston, we went back to M. D. Anderson today to meet with Dr. Keating's nurse to see what the status of my inclusion in the new drug study might be. We were met by the research nurse in the waiting room and she had a fifteen-page permit in her hand. She said I was in! She started telling me about the schedule we'd need to follow and how we'd be getting the drugs, one of which is my old friend Rituxan, which is given by IV infusion, and the other is the research drug PCI 32765, which is in a capsule form. I asked, well, what if the PET scan isn't normal and what if the biopsy shows Richter's. Oh, don't worry about that, she said, they had already reviewed the PET scan and it was okay. Wow!

So we found out that we'll be starting the new drug clinical trial later this month, on March 27th, to be specific. I'll need a series of tests first; a bone marrow biopsy, CT scan, EKG, many blood evaluations and another physical examination. And then we'll need to come to Houston weekly at first, and then monthly for about six months. But hopefully the drug will work as well for me it has for the first folks on whom it was tested. I will get the Rituxan weekly for four weeks and then monthly for another five months. Once I start the pills of PCI 32765, the day after my first Rituxan infusion, I'll be taking it daily for at least a year, barring significant complications.

Then Dr. Keating's clinical nurse asked me to come in to the clinic to talk with Dr. Keating between patients. I was happy to do so. When he had a chance to break free between his scheduled patients, he came in to our room and we talked about getting me into the study group. Only 40 patients are being accepted into this group! I believe only 117 were in the first, Phase One group (in which the drug’s safety and efficacy were evaluated, and a standard dose defined) so it's a special and select group of folks who have been picked to test this drug. I'm really honored and hope that my experience will help me and lots of folks who come after me. Since the PET scan was normal, or at least, cleared me of having the Richter's Transformation, I asked if I needed the needle biopsy which was still to be scheduled. Dr. Keating said he'd rather I didn't have the biopsy. That was good enough for me, as I didn't relish the thought of having a needle stuck deep into my belly to get cells from my tumors. So, after talking with Dr. Keating, we went back to the transplant clinic and canceled the biopsy. And with that, we were done.

We plan to drive home tomorrow and get out our calendar to schedule to plan out our weekly and monthly trips to Houston. We'll have to plan our life around these trips but that's okay. I look forward to it.

The next message will be about starting this new, experimental drug and what it’s like being on it. I’ll also spend just a bit of time explaining how this Bruton’s Tyrosine Kinase Inhibitor drug actually works. I know you can’t wait!

More to come....

Dave

PETs and Gorillas

Dave’s Great Adventure
Book 5, Chapter 1, Verse 4
February 29, 2012


Hello again. Today was a much better day.

We started out with me getting my PET scan (Positron Emission Tomography, if I'm correct). It's a scan which combines a CT scan with a nuclear medicine scan using some sort of radioactive isotope of iodine. Apparently malignant cells are aberrantly hyperactive metabolically and gobble the stuff up faster than normal when the radioactive iodine is attached to a molecule of sugar. So they do a CT scan of my body, and then overlay that scan with a scan of the overly active parts of my innards. Sounds easy, and actually it is, but the prep for the study...well, I wasn't ready for it.

I had been told I couldn't eat anything for six hours before the study, so I expected that I couldn't eat or drink anything after midnight, as with many tests and surgeries and such. So, we bought some carrot cake for me to have as a midnight snack and I ate it about 9PM. Only then did I find (on-line) the M. D. Anderson instructions for the scan, which included recommending a high protein meal the evening before and avoiding carbs. Oh well.... Turns out I could drink as much plain water as I wanted, too, even up to test time. I really should read the instructions to these things, but I suppose I think I know too much to be concerned with such details.

Anyway, we went up to the med-cen again today and found our way, with the help of a golf cart shuttle system, through the mazes of buildings and skyways. M. D. Anderson is a small city, self-contained with villages, parks, paths, hotels and restaurants. It would take a while to find your way completely around the place. But we're learning. We found our way, with the shuttle help, to the Mays Clinic where the PET scans are done. It's in a completely separate building from the main CT scanners, curiously, perhaps a quarter of a mile away. I had, according to my schedule, three appointments there. The first was "prep," followed by "injection and localization" and then "lymphoma restage." I checked in and sat down. A short time later my name was called, and I went to the back. Turns out all my appointments all ran together and I didn’t see Kathy again for several hours.

The "prep" involved getting out of all my clothes which had metal, like my jeans, and getting into scrubs. Then I had an IV put in my hand. Then, I was told, I would "rest." "Can I read the paper?" "Can I get my cell phone?" The answers were "No, you will rest. And uncross your legs." I was commanded to "rest." I joked, "Well, can you give me a Valium or something so I'll rest?" But they took me too seriously, so I told them that, no, I really didn't need a pill. Then they turned down the lights and left on a backlit picture of a park, with a pond and daffodils in the foreground with red and purple tulips in the distance, in front of me. I rested. ZZZZZ

About 30 minutes later a tech came in with a syringe encased in a heavy metal case. It was the radioactive iodine, with which I was going to be injected. He told me what it was and what he was going to do, he did it, and told me, again, to rest. For an hour. So I rested. With my legs uncrossed. ZZZZZ An hour later, another tech came in, and told me we were going to get my scan but first I was going to be given the opportunity to go to the bathroom, which I did. I came back out and sat in the chair where I had been told to wait. A tech walked by, looked at me and said, "Uncross your legs." I'm unclear, still, about the prohibition on crossing one's legs. Soon I was taken to the next room where the scanner was and was placed on the machine, which was, generally, like an MRI machine with a large tubular structure, which I was moved into and out of sequentially. It took, maybe, 30 minutes and it was all over. I guess the results will be available in a day or so.

Meanwhile I still wondered what my longer term plan was to be. After my PET scan, I had no further appointments at all. When I last saw Dr. Keating, the plan was to get on the new PCI 32765 protocol, but when that plan fell through, I was left with no follow-up appointments or scheduled tests. Before I left his clinic, Dr. Keating's nurse had told me that he didn't like to be told "No," and might argue with the protocol managers. But, after Gracie came back yesterday and told me that no exceptions could be made after having called them, I gave up.

But, Dr. Michael Keating is an 800 pound gorilla within the CLL community. If you Google his name and CLL, you will find probably hundreds of references and scientific articles by him. Plus, he runs his own CLL research organization, the CLL Global Research Foundation, which sponsors research all over the word. He lectures every month in locations around the world. Just this week he has returned from lectures in Hong Kong. So when I went back to the clinic this afternoon to see his nurse, she told me that HE WANTS ME to get on the PCI 32765 protocol and was still "in discussions" with the protocol manager. She told me to check back tomorrow by mid-morning to see if there had been any change. By now it was mid-afternoon so, we went back to our motel to get some rest.

Soon the cell phone rang. It was Gracie, the research nurse. She said that the protocol managers, after "further consideration," had allowed me to get into the protocol. Amazing, just amazing. The logic they used to make this exception seems to be that they decided the Rituxan which I had been given in connection with a stem cell collection in 2004 didn't count as "treatment." It was just used to mobilize my stem cells for the collection we did back then. I don't really know what difference that should make, but I'm happy it happened. Rollercoaster starting up, safety bars engaged, clank, clank, clank, clank....

But I'm not totally out of the woods with this study, yet. My understanding is that yet another exclusion from the protocol is the presence of Richter's Transformation, and we still don't know if I have this or not. My labs and exams are suspicious for it. The PET scan from today and the biopsy soon to be done will sort this out. Tomorrow will bring more information and hopefully no bad surprises.

And, as always, more later.

Dave

Irony of Ironies

Dave’s Great Adventure
Book 5, Chapter 1, Verse 3
Irony of Ironies


February 28th was a tough day. We got whipped one way and then the other. The day before we had gotten the news that my labs indicated the possibility that I had developed the deadly Richters Transformation form of CLL which I've previously mentioned. It happens in about 10% of all folks with chronic lymphocytic leukemia. The transplant folks mentioned that one of my lab tests indicated this possibility (specifically my LDH, lactic dehydrogenase test, which was elevated).

So the next day we went to see my CLL expert doc. You may remember that last August when we found that I had the p53 mutation (which has a much worse prognosis than the form of CLL without this change) he started me on Arzerra to help me hold my own against the disease while they were waiting for some new drugs to be available. He picked the Arzerra because it's an antibody type drug, and as such, does not damage the body's immune system like most chemotherapy regimens. It worked at first but became ineffective after about five months. When I was found to have masses growing in my belly on CT scan a couple of weeks ago, my doc talked to Dr. Keating and was told there was new clinical trial which was just opening up at M. D. Anderson and that I was "Number One" on his list for it. I wasn't told what the trial involved but figured it might include the use of the new Bruton's Tyrosine Kinase drug, PCI 32765, which I've also previously mentioned. More about it later if I actually end up on the drug.

So we saw his nurse practitioner who examined me and went over my labs. She confirmed that the disease was progressing and that my labs indicated the possibility of Richters, though we still haven't confirmed this. She also mentioned that with my new finding of possible Richter’s Transformation, I wouldn't be a candidate for the new PCI 32765 drug. That was an incredible downer to hear. I had been anxiously awaiting this new stuff which seemed much too good to be true; a pill a day without side effects, with a little Rituxan (another antibody type drug) thrown in on monthly basis for a few months. So, after hearing that, Kathy and I sat in the office, glum with disappointment while we waited for Dr. Keating to come in.

But then he came in with a big smile on his face. "Just in time!" he said. The new drug is available and it will be perfect for me, he said. It shrinks tumors, even aggressive ones, and increases antibody levels, reduces infections, is well tolerated, and so on. Folks have been on it for 18 months or more without any serious side effects. He said he'd send in his research nurse to sign me up for the new clinical trial. Wow! After, being so bummed after our discussion with Dr. Keating's nurse, this was a complete turnabout. Kathy and I mentioned how rapidly things seem to change in my disease and that we've been through the CLL roller coaster more than one time. This was yet another up and down and up.

As soon as he left the office for his next appointment his staff started trying to arrange a few things that I would need before starting on the new drug, the PCI 32765. I would need a bone marrow biopsy and an infusion of Rituxan. They were working in getting these set up ASAP, later the same day.

Then Gracie, the research nurse came in. She started to sign me up for the protocol but stopped short, very early on, as we discussed my past treatments. She said she hadn't realized that I'd had Rituxan on three previous occasions (I had had the drug in 2002, 2004 and 2008), thinking instead that I'd only had it twice before. Then she said the new protocol excluded anyone who had had the drug more than three times. "But," I protested, "I have only had it for a total of three times so far!" Yes, she said, but you also had Arzerra earlier this year and that counts as a Rituxan infusion, as it's in the same category of drug.

She then left to try to talk to Dr. Keating, who by now was doing a webcast for the Leukemia and Lymphoma Society, but in between questions and comments, he was texting her back. "WHY!!!" he texted when told I wasn't eligible for the new study. Gracie apparently contacted the folks running the protocol, looking for an exception, but none was forthcoming. After about 45 minutes, she and Dr. Keating's nurse came back to say that it looked final, that I wasn't eligible.

So, here is the incredible irony in all this. The drug that Dr. Keating gave me to try to keep me healthy long enough to get me involved with the new drugs that are just now coming into availability, the Arzerra, is the drug which now makes me ineligible to take part in the study, now that it's finally available. That's just amazing. Depression to elation to depression in 15 minutes. The roller coaster. Again. Tomorrow I have a PET scan and at some time thereafter (soon I hope) they'll schedule a fine needle aspiration/biopsy of one or more of my tumors. I'm not sure what that'll lead to in the short term, but if I in fact have Richter’s, I think I'll be starting on high dose chemotherapy soon and the stem cell transplant will be expedited. But, that's just conjecture right now. Right now we have no concrete plan, but we'll have to have more details before we leave Houston. I hope to talk to Dr. Keating and his staff again tomorrow to see what they say is the next step, since the step we were left with today fell off a cliff. Stay tuned.

Dave

First Update From Houston

Dave’s Great Adventure
Book 5, Chapter 1, Verse 2
First Update From Houston


We had a wonderful trip to Antarctica. We were kept busy with multiple daily landings and cruising out among the wildlife and icebergs in the inflatable zodiacs that we used to go from ship to shore. We were tired from all the activities but it was worth it. Even the 5AM awakenings (which were 2AM Dallas and body time) were ultimately worth it as there was so much to see and because we had to make the most of the precious few days we had available to spend there. It was a special time. This place belongs on everyone’s bucket list.

But as soon as we got home we had to prepare to leave again, as we had to be in Houston for multiple test and evaluations within five days. So, Kathy worked on huge loads of laundry while I caught us up on bills and errands. Then we packed up again and drove to Houston, a drive we have made many, many times in the past five years or so. I was expecting several days’ worth of appointments as we had a lot of ground to cover and many questions to answer about my condition and its possible treatment.

First, as I suspected, they had added on some appointments to the two days' worth that had previously been scheduled. This was mostly because of the many large masses found in my abdomen on the CT scan I had just before we left on our trip a couple weeks previously. So, our originally planned two-day trip turned into a four day “vacation.”

We first met the very nice folks at the transplant clinic and as far as they're concerned, I WAS having a transplant, probably within 3-5 months! There was no question about it! And here I thought we were just going to meet some folks and have some questions answered. My transplant doc, Dr. Khouri, is one of the pioneers of transplant procedures for leukemia. He says, and I've heard this before, that a transplant is the only possible cure for folks like me with the p53 mutation, which I described in some detail a few months ago. So, “full steam ahead,” according to him. He has scheduled a PET scan for a couple of days from now (to check for malignancies) and a lymph node biopsy at some time yet to be determined, but pretty soon, if they can possibly arrange it. They're still actually thinking that I may have the deadly Richter's Transformation lymphoma, based on some of my labs. The PET scan and biopsy will be important to confirm or deny this possibility and will help treatment.

I probably need to stop at this point to explain a couple of things. First I want to tell you why this new mutation I have, the p53 mutation, is so deadly. The p53 gene is called the “tumor suppressor gene.” It tells cells to die when they are damaged. Now, most chemotherapy works by damaging cells so they will die. The alkylating agents and purine analogs that make up most standard chemotherapy regimens, like the Fludara and Cytoxan I’ve had in the past, work on this principle. They damage a cell’s DNA so that they will die. But now that my disease has the p53 mutation (also called the 17p deletion but meaning the same thing), my cells don’t know to die when they’ve been damaged. That’s why my disease is now so resistant to treatment. And that’s why most leukemia experts now strongly urge folks like me to get a stem cell (or bone marrow; same thing) transplant as soon as possible after finding out we have the deadly mutation. But these transplants can have their own risks of death, disability and numerous complications.

But Dr. Khouri quotes “only” a 5-10% mortality from the transplant procedure, better than the 15-25% death rate I've been hearing from most transplant experts. The success rate in curing my disease is said to be 50-70%, depending on my disease and how well might respond to pre-transplant chemotherapy.

We met with the stem cell coordinator also. We already had some cell-typing results showing that my sibs don't match me, from tests done back in 2002 when I first got sick. My cells were also partially tissue-typed during that study. Based on the partial HLA (human leukocyte antigen) tissue typing that was done back then, she searched the marrow banks' data banks and found...get this...70 potential donors! Now, this number will decrease somewhat as they get the final parts of the tissue typing done (I had ten tubes of blood drawn today to get a complete HLA panel done) but as she said, all we need are one or two potential matches. Interesting news. I wonder where all these folks are. Since my dad was full-blooded Swede, I'm half Swede. I wonder if all these folks are in Stockholm or somewhere. Or maybe in the upper Midwest where lots of Swedes settled in the 1800s. Anyway, it will take, she said, 3-5 months to get a donor lined up, which is what limits and sets the time frame for the transplant. We should hear within about ten days about whether a match has been definitely located, though not necessarily if that match is truly available just yet (are they still alive, willing to donate, free of disease, etc.).

If/when I have the transplant, they'll want us to move down to Houston for 3-4 months. Wow! They have given us the name of a social worker who can help us find nearby housing, and my cousin, Amber and her husband, have also offered to put us up at their home west of town if need be. There’s also a huge hotel complex right across the street from M. D. Anderson which is in some way connected to the workings of the medical complex. It even has a skybridge connecting it to the cancer clinics. When I have the transplant I'll be in the hospital for about three weeks and then have to have daily visits for a couple of months! Sounds pretty intensive.

By the way, I had to sign a contract saying that I understood that my kind of transplant would cost anywhere from $560,000 to $1,100,000 or so! “But,” I was told, “that will include today’s consultation.” Man, I’m glad that the consultation wouldn’t be an additional expense on top of the million bucks.

I see my leukemia specialist tomorrow to see about whatever clinical trial he has in mind. The only thing I can see that would interfere with getting the stem cell transplant in the coming months would be if the drugs from this new clinical trial worked much better than anything else ever has. We'll find out his thoughts on this topic tomorrow.

And that's all the news for now. This adventure keeps on getting more exciting.

Bye now,

Dave

Intro to Book Five

Dave’s Great Adventure
Book 5, Intro
April 2, 2012
Astounding…just astounding!

We’ve had an extraordinary spring here in north Texas, with mild temperatures, gentle rains, lots of sun and perfect conditions for new growth. Everywhere one looks the trees are covered with fresh green foliage. And the byways, pastures and meadows are covered with a soft green growth of grass and flowers. Our famous (at least here in Texas) bluebonnets have formed wonderful carpets of blue almost everywhere you look along the roads and they’re interspersed with patches of magenta from the clover flowers and yellows from the daisies and such which are also blooming in profusion in many areas. The breezes have been gentle as well, unlike the typical screaming winds we often have in north Texas in spring. It’s been just about perfect and, I think, it’s the nicest spring we’ve been privileged to experience since our move back to Texas six years ago. It’s a beautiful season of renewal, new life and new hope.

I haven’t written anything in my long-running DGA series in a while, not because nothing has happened, but to the contrary, because we have been so very busy in the last two months. So much has happened that I haven’t been able to keep up. What little I’ve written I haven’t completed and only my family and a few friends have been kept abreast of what has occurred. And some incredible things have happened, both good and bad. I thought now would be a good time to try to catch up. But, since so much has occurred, I’ll break the update into a few shorter stories and send them out a bit at a time.

Some of my family and friends will recognize earlier versions of the chapters as I’ll base them on letters I have shared with them over recent weeks, but many of you will see this stuff for the first time. But the story is just amazing, at least to me and Kathy, in the number things that have occurred in such a short time, and the timing of so many events. I’ll be sending them on shortly. If they become tedious, the “delete” button can be your friend. If you find some of this interesting, I’d love to hear from you as I get the stories out to you.

Dave

Bad To Worse

Dave's Great Adventure
Quick Update
February 8, 2012


Just a quick update on what's going on with me. I'd been wanting to do another DGA but not enough info has been available yet.

I have been waiting and waiting to hear something, something, from M. D. Anderson. I've e-mailed repetitively and gotten some hints from Dr. Keating's nurse, but no definitive answer on what's happening next. I'm supposed to be enrolling in some new clinical trial. I'd like to know something about it.

Meanwhile, last Friday, I got a call from my local doc's nurse. He was ordering a kidney ultrasound because my creatinine had gone up a bit. I thought that was weird as I was wondering what they could possible see on a sono that might be causing it to go up a bit. Normal is about 1.0; mine had been about 1.2 to 1.4 recently, but now was 1.6. So I had the US done. It showed slight enlargement of the left kidney and "soft tissue masses" impinging on the bladder. As soon as that report hit my doc's desk, he ordered an immediate CT scan of my abdomen and pelvis...actually dragged me out of the tub the next morning to get back down to the hospital. He had to hurry as we're supposed to be leaving for Antarctica (a long way from any medical care) tomorrow!

So, we got down there, drank the lovely 24 oz. drink of "contrast, waited 90 minutes and had the CT. It took all of maybe 5 minutes.

The CT shows widespread adenopathy (either swollen lymph nodes [hopefully!] or a new tumor, a lymphoma) in my belly, along my aorta, around my bowel, and some up to 6-8cms in size (tennis ball to orange size) near the bladder. That's not good news.

Many calls went between me an my local doc and my local doc and Dr. Keating. They say nothing is going to change in the next 12 days so I'm free to go to Antarctica, but some stuff is gonna happen when I get back. I'm not yet sure what all is going to happen, but I did get a clue about the clinical trial.

I was thinking that the CT findings might represent what's called Richter's Transformation, a deadly form of lymphoma that can CLL morph into about 10% of the time. That would leave a predicted longevity of 6-8 months. But I guess my docs don't think so, as they're letting me go ahead, and they're still planning on enrolling me in the new clinical trial. If I had RT, I would probably need intense chemotherapy ASAP followed almost immediately by a bone marrow transplant.

But Dr. Keating says he still plans on enrolling me in the clinical trial when I get back, and I will be the very first on the list. He believes it will be approved by the end of this week. Great, but I still don't know what the trial involves. But...I'm Number One!

After we leave town tomorrow we will be out of telephone and, for the most part, e-mail contact until we get back on the 21st. So, I won't know any more until we get back to town, and may not know any more until we get back to Houston in late February. We have appointments on the 27th and 28th.

And that's all for now. More later.

Dave

Arzerra and Beyond...But To Where?

Dave’s Great Adventure
Book 4, Chapter 1, Verse 6
January 13, 2012


[[[ “If you want to make God laugh, tell Him your plans.” --Anonymous
I’ve used this quote a couple of times over the years but it’s again appropriate. We only “think” we have our lives planned out. The following message was started in mid-November, but then I didn’t get back to it for quite a while. Meanwhile, things have changed again. Read on. ]]]

---November 14, 2011---
I think there are real signs of hope with this new stuff. I believe it’s working better than I thought it might.

When I last wrote about what was going on I had just finished Phase One of my Arzerra (ofatumumab) treatments. The treatments had begun rather abruptly in August. In mid-August, after waiting five weeks to hear the results of the cytogenetic tests which I described in excruciating detail in my last letter, my local doc got the details about the development of my worrisome p53 mutation and the plan for treatment, from my doc in Houston. With that information, we began the Arzerra almost immediately, within a week. In fact, we started the first dose of the Arzerra on August 23rd, our 42nd wedding anniversary. I try to make our anniversaries memorable for Kathy.

The Arzerra infusions have gone very well. The first phase of the treatment was eight weekly infusions. The side effects have been relatively minimal, all things considered, and that’s because I haven’t been getting any poisons this time. With all my previous treatments I had combinations of drugs which included poisons, as most chemotherapy targets fast growing cells, like cancer cells. The problem is, of course, that all fast-growing cells in one’s body are not cancer cells, so normal cells get affected as well. And that leads to side effects; the nausea, hair loss, mouth sores, etc. One of the drugs which I had in all three previous chemotherapy regimens is some stuff called cyclophosphamide, which advertises its role in chemotherapy by its trade name, Cytoxan. That’s a play on its activity within the body. “Cyto-” means cell; “toxin” means poison. Therefore, its trade name, Cytoxan, or “cyto-toxin” literally means “cell poison.”

But the Arzerra I’m now getting is not a poison, per se. It is pure antibody, an antibody directed against white blood cells with a protein called CD20, which is on the cell membrane of all CLL cells (CLL cells are actually abnormal B-lymphocytes, which are the kind that make your antibodies). It attaches to the CD20 protein and allows the body’s immune system to bore a hole in the leukemia cell’s membrane, popping it rather like a microscopic balloon. That’s the good or even great part about the antibody treatments. They target only a specific population of cells, ignoring the rest. But when they simultaneously pop billions of leukemia cells, all those dying cells spill their cell contents into your blood stream, and all those proteins, histamines, DNA and such, can clog your kidneys, cause severe allergic reactions, breathing problems, low blood pressure, and the like. Because of this possibility, before each treatment we are given antihistamines and steroids, to suppress the allergy-like reactions, and we are given the drug very, very slowly. The first treatment I got took us from 8:30 in the morning until 6:30 in the evening to complete. As I got used to the drug and as my white blood cell counts dropped (giving the Arzerra ever fewer “targets” to seek out), we were able to start giving the drug faster and faster and by the end of my eight consecutive weeks of treatments, we were able to complete the infusions by 3:00PM.

By the way, my clinic billed about $25,000 for each weekly treatment. These newer chemotherapy drugs are wonderful but they are also fantastically expensive.

But the Arzerra has worked extremely well, dropping my white blood cell counts from a pre-treatment level of just under 80,000 (normal is about 3,000 to about 9,000) to about 4,000 after the eight weeks of treatment. Now, that count is in the normal range, but the count still is not “normal,” as another test that looks for abnormal white cells in my blood, determined that 35% of my remaining white blood cells were still leukemia cells. But that’s not really a surprise. The Arzerra really wasn’t expected to put me into a complete remission anyway.

Despite that minor point, things are going very well, better than I’d hoped. When I started the Arzerra I was told that there was only about a 50% chance I would have a response to the drug because I now have the more aggressive leukemia mutation. Well, I’m obviously in the 50% of the population on whom the new drug works. Then, after we finished the eight consecutive weeks of infusions, and waited a full four weeks for the start of my monthly treatments, my white counts continued to drift down. In other words, despite stopping the drug for a month, my disease didn’t come charging back. I hope this trend continues. So far it has. I’ve had one of the monthly infusions and my white counts have remained around 3,000 or so. My next treatment will be in early December and will continue monthly through next February.

But just about any treatment will have side effects, and the major side effect that one gets with the Arzerra stems from its ability to seek out and kill only white blood cells with the CD20 marker on its cell wall. Unfortunately, all NORMAL B-lymphocytes (the ones we depend on to make our antibodies) ALSO have the CD20 antigen. So, that means that while the Arzerra is wiping out billions of leukemia cells, it’s also taking out a large number of my normal lymphocytes, too. That puts me at risk for infections as well as other tumors and so forth. But, that’s the chance I have to take to be able to hold my disease at bay long enough to try to find another, better, long term treatment and possibly a cure. In any case, the plan all along with the Arzerra has been to give me this drug over about six months, then wait perhaps six more months until it stopped working and then do…something. What, exactly, has been unclear.

I’ve been trying to re-evaluate my expected longevity based on the results of the Arzerra so far. When I first found out I had the p53 mutation, which I already knew was bad, I went back to my sources, one of which is an excellent CLL web based resource called “CLL Topics,” a well researched, critical review of all things related to CLL and its treatment. Here I found the article which noted that average longevity was just 13 to 15 months! Just over a year. But, it’s now been six months since I started the Arzerra and things seem to be going well. Since the CLL hasn’t stormed back between my monthly infusions so far, I’m guessing I may have more than a year left after all. Other sources I’ve checked suggest average longevity is perhaps 1 to 2 years and another source says 2 to 3 years. In any case, if these are accurate, those are AVERAGE numbers meaning half the patients will live longer, the other half less than that. And all of us cancer patients just KNOW we’re going to be in the longer-lived half. It’s unclear also, if these numbers are for treated or untreated patients, and if treated, what the treatment was. We shall see. In any case, I’m feeling much too normal to think that I’ll be dead within the year.

---January 11, 2012---
Things have changed. I wrote all the above about eight weeks ago but then couldn’t get back to it to finish the report. I had been very encouraged by the results of the Arzerra treatments since they seemed to be holding off the advancement of the disease. But, in the last several weeks, though my lab tests still show improvement, my lymph nodes are again enlarging in my armpits and some are now growing in my neck as well. Not good. My local oncologist here in Denton recently reported this to Dr. Keating, my doc in Houston at M. D. Anderson, and we got an unexpected phone call a few days ago.

Dr. Keating called back with some surprising and potentially very exciting news. He has cancelled the last of my four monthly infusions of Arzerra, since it hasn’t worked all that well in the last couple of months anyway and, after I’ve been off the drug for a month, which will be at the end of January, I am to get in contact with him again to talk about enrolling in a clinical study of some kind. What kind of clinical trial? I don’t yet know. When will it start? I don’t know. How long will it be? I don’t know. What are the risks involved? I don’t know.

He had been talking about possibly going to a stem cell transplant in the very near future. In fact, I have several appointments set up in late February to speak to the transplant team in Houston. That seems to be the new approach to treating folks with the p53 mutation. Rather than try multiple treatments of chemotherapy which will likely not work, they’re going to transplantion sooner in the course of treatment, as the transplant works better when done in patients who are not critically ill. Of course, with a 15 to 25% mortality rate associated with transplant, it’s a hard sell to folks who don’t feel or look critically ill, but that’s the current trend and I have been rather expecting to be going that direction in the near future.

But, now Dr. Keating is talking about enrolling me in a clinical trial which is just now opening. Unfortunately for me, the message I received did not mention what the trial would be, so I’m a bit in the dark. We have talked about the new, rather unfortunately named “btk inhibitors” like CAL 101 and PCI 32765 (this would be a good time to use Google!) which is what I am hoping he’s going to get me into. These seem to have great promise in destroying the disease and seem to have minimal side effects. The treatment consists of simply taking a pill daily, with most patients having minimal side effects. That sounds too good to be true. I mentioned the unfortunate naming…. The drugs are called “Bruton’s tyrosine kinase inhibitors,” hence the “btk” designation. But not too many years ago there was a serial killer in Wichita, Kansas who went by the name of the “BTK killer,” for “Bind, Torture, Kill.” Well, this stuff kills CLL cells, I suppose. Maybe it tortures them too!

Other possibilities for the clinical trial include a combination of drugs using lenolidamide, a derivative of the notorious birth defect causing drug Thalidomide. It is also a pill form of anti-CLL drug, but is frequently used in combination with other drugs such as Arzerra. And then there are the new CARs treatments. This stands for “Chimeric Antigen Receptors” and is the basis for the treatment that made a big splash in the press last summer, as having cured a few patients. It involves treating one’s own T-lymphocytes and training them to attack the leukemia cells. This has worked well in a very few patients, but thus far there is no long term follow-up, just a year or so. It may take the place of stem cell transplants some day, but is extremely labor intensive and expensive, since it involves taking a patient’s T-lymphocytes out, treating then, and reinjecting them into the same patient. Every patient will have to have a personalized treatment with his/her own T-lymphocytes. My cells wouldn’t work for someone else, and vice versa. More about T-lymphocytes later, if I end up in that kind of program.

Or, the clinical trial could be something else entirely. The message I got was third hand, having gone from Dr. Keating to my local doc’s message machine and then passed to my doc’s nurse, who called me. If there were more details in the message, I didn’t get them. I’ve sent a message to my team in Houston asking for more information but have yet to hear back from them. Wish me luck.

And so, that’s the latest. My disease is getting aggressive again, the Arzerra isn’t working as well, and now I’m off it entirely. And, some experimental medicine looms in my future, probably within a month or so.

But despite all this, I’m still doing pretty well. I don’t feel ill, I get to do most of the things I want to do if I don’t do too much of it and, really, the only consequence of my disease that I can discern is that I feel more tired than I‘d like and my muscles ache some. But hey, I’m 65 years old now. Maybe I should feel more tired that I used to.

And that’s all for now. I’ll be back when I learn more about what’s coming my way in the next few months or so.

Dave

***As I start yet another chapter in my battle against leukemia, I am reminded of this quote:
--“It is never too late to start. It is always too soon to quit.”—Norma R. Lineberger--
Norma worked for the Legal Defense and Education Foundation, and died of leukemia in September 2009.

www.adventureswithleukemia.blogspot.com