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