Thursday, May 24, 2012

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,

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!


“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; )