Dave’s Great Adventure
Book 4, Chapter 1, Verse 5
November 2, 2011
I didn’t expect this. I was doing so well. I felt good and was getting along just fine. I mean, I had done all those half-marathons, right? How could I be this sick?
We had a busy spring and early summer. My disease, which had relapsed the previous year, had been advancing faster with my white counts doubling every couple of months or so. I was expecting to have to do more chemotherapy by about mid-summer, so we packed our travel plans into the early part of the summer. We went to Oklahoma City for a marathon (in the rain and cold) in May, went to San Diego for one there in June. We went to a reunion of my Vietnam vet buddies in Tampa in late June, to a family reunion in North Carolina in July, and more. In the midst of all these trips we went to Houston in early July to see my doc there, who is one of the world’s foremost gurus in the management of chronic lymphocytic leukemia.
I was still feeling well; maybe a little more tired than I’d care to admit, but over all, I was doing okay except that my lab tests told another story. My disease was advancing rapidly. I talked things over with my doc, Dr. Michael Keating, and we went over some possible treatments. I say “possible,” because after you’ve been treated for this disease once or twice, there are no standard “best” treatments anymore, just lots of possibilities.
But he wanted to do a few more cytogenetic (chromosome) tests before we started anything, to help guide us to, hopefully, the best of our options. He said I’d hear something about the test results “in a couple of weeks.”
Now, to me, “a couple of weeks” mean exactly fourteen days. When I didn’t hear anything in those fourteen days, I made a series of calls to M. D. Anderson and played phone-tag for a few weeks, never getting any information about my lab tests. I was getting worried.
Meanwhile, a long-scheduled appointment with my local oncologist came up so I saw him and explained how things were going. We also talked over some possible options for treating my disease and then he said he’d call Houston and get the information for me. I was grateful, as I really wanted to hear the results of the cytogenetics.
Later that day I got a call from my local doc. He had heard from Houston. He had news, but the news was just horrible. He talked for a while but all I remember was something like “…blah, blah, blah…p53 mutation…blah, blah…Arzerra…blah, blah…50% chance of it working.”
What this means
When I got sick with this disease, chronic lymphocytic leukemia, almost ten years ago, it was only “one” disease. The doctors and researchers working with it knew that some folks with this disease died in two or three years while some folks lived, without needing treatment, for maybe twenty years or more. They knew that some patients responded well to treatments while others didn’t. They just didn’t know why. But about eight years ago they found that CLL is actually a group of diseases, differentiated by the chromosomes in the leukemia cells and several other protein “markers” exhibited by the disease. There are at least seven or eight major sub-groups of CLL and perhaps more, and survival and resistance to treatment varies greatly among the groups. By looking at the mutations of the chromosomes in your cells physicians can tell how long you’ll likely survive and what treatments might work best for you, and also how aggressive they should be with trying to treat your disease.
A couple of years after I got sick, they tested my chromosomes. They were 46XY, normal male chromosomes, as you’ll no doubt remember from your high school biology course. That was very good, as normal chromosomes were a marker of easier to treat disease and generally longer survival. Curiously, however, there is one mutation called 13q- (13q deletion) which is even better than normal chromosomes in terms of survival. But there are also several possible mutations of the disease that indicate a more aggressive and harder to treat disease. These can be ranked in order of increasing resistance to treatment and subsequently, shorter survival. And since patients with CLL tend to mutate to harder to treat forms of the disease over time, my doc in Houston was retesting my disease to see if I had mutated. And the tests in July at M. D. Anderson now showed that I had the p53 mutation, also called the 17p deletion (17p-), one of the very worst of the several variations.
Details
I’ll include a short description of what this genetic shorthand means for my friend Steve who lives in either Englewood, Colorado, or Centennial, Colorado, or maybe unincorporated Arapahoe County (I don’t remember which for sure), in the Denver suburbs. He likes details. Anyway, normally we all have 46 chromosomes per cell, 22 pairs of “somatic” chromosomes plus our sex chromosomes, the XX for females and XY for the guys. The other 22 pairs are numbered 1 though 22. Also, if you remember looking at pictures of chromosomes in textbooks, they look rather like stretched out X shaped figures, usually arranged with shorter arms at the top and longer arms at the bottom.
(By the way, our chromosomes don’t just stretch out and pose for the pictures that we see in books and magazines; they have to be manipulated with various chemicals to make them look this way. Normally they’re all balled up in a tangled mass in our cells’ nuclei.)
The short arms at the top of the chromosomes are called the “p” arms; the longer ones at the bottom are the “q” arms. If you took a part of the “q” arm off a 21 chromosome, it would be called a deletion and written as 21q-. Sometimes extraneous genetic material gets added onto chromosomes. These are additions, written as 21p+, for example.
The p53 mutation
So, now I have the dreaded p53 mutation, also called the 17p- mutation, the 17p deletion. Over the last few years my disease had changed, which is what it typically does for most patients with CLL. p53 is a gene, the “tumor suppressor gene,” which normally resides on the short, “p” arm of the 17 chromosome. Now it’s not there; in my case; it’s been “deleted” somehow. This is a very important gene which, as its name suggests, suppresses tumor growth and malignancy formation. Now I don’t have it anymore. When you read about the p53 mutation in CLL you see things like, “much more difficult to treat,” and “more aggressive disease” and “average survival of about 13-15 months.” Our friend Larry Love recently died here in Denton. Larry had an extremely rare case of metastatic basal cell skin cancer. Basal cell cancers are generally among most easily treated of all skin cancers yet in Larry’s case, this usually innocuous skin cancer spread throughout his body and despite three years of treatments, he died because the disease could not be controlled. Larry’s skin cancer had the p53 mutation. The p53 mutation is not good news.
Arzerra
This is the drug my doc picked to treat my disease this time around. Now, if you’ve been reading my stuff for any length of time at all, you’ve read about Rituxan, which has been a part of my three different previous chemotherapy regimens. Rituxan (rituximab) is a mouse-based antibody against leukemia cells. It targets a specific protein (called the CD20 receptor) that all CLL cells have. It works extremely well at doing this. The only problem is that being mouse-based (or “murine”), it itself is a foreign protein and humans can form antibodies against these murine antibodies, inactivating them.
Arzerra (ofatumumab) is similar to Rituxan in that it is also an antibody which attacks the CD20 protein receptor. It has been around in Europe for a few years but has only been approved for use in the US for about 18 months. In Europe it is called HuMax, which reflects the interesting fact that it is a humanized antibody against the CD20 site. In theory at least, it should be better for attacking the leukemia cells since humans shouldn’t create antibodies against it. In addition, it binds more tightly and for a longer time to the leukemic cells than does Rituxan, if you believe the manufacturer.
Interestingly, when reading the prescribing information that comes with this drug, the manufacturer states that it will not cure, put into remission or reduce the symptoms of any patient with CLL. This is an amazing thing to put in writing. It must either be something required by the FDA or perhaps it’s just their lawyers lowering expectations. Otherwise, it would be no more than a placebo drug!
I was very disappointed, at first, to be prescribed single-agent therapy with the Arzerra. My disease is now much more aggressive, yet I was being given a drug that would be very unlikely to put me back into remission. Studies of the drug in patients with my mutation showed only about a 50% rate of successful treatment. From the very beginning of my adventure I have wanted to be as aggressive as possible in treating the disease. Here it looked to me as if we weren’t doing as much as we could. I had found, on-line, several studies of Arzerra being used in combination with other drugs with apparent good success in short term studies. I wanted to use lots of drugs. I wanted to kill the leukemia. I want to rid my body of it. That’s always been my goal.
But in the larger picture, moderation may be better in treating my disease. Yes, it’s much more aggressive now. Yes, my survival seems to have been shortened by the mutation. Yes, it’s harder to treat. But, there are several, and I mean several as in four to six or so new therapies which are just over the horizon and at least some of these depend on a patient’s functioning immune system to be effective. In the past my chemotherapy regimens have included the use of several toxic medications which have vigorously attacked my disease with a “chemical machete,” clear-cutting my marrow, taking away good cells as well as bad, severely damaging my immunity. The use of these drugs now could jeopardize my ability to use some of the newer therapies which are still in the study phase and just on the verge of being more widely available. Three of these are in pill form and are taken daily, at home, much like the vaunted drug Gleevac, which has shown such remarkable success in treating (but not curing) another form of leukemia known as chronic myelogenous leukemia (CML). And there are studies using gene therapy to train one’s own T-lymphocytes (a topic for another day) to attack and kill the leukemia cells. This therapy has reportedly “cured” two people in a study recently released by the Abramson Cancer Center in Philadelphia, though the follow-up was a short ten months. And if nothing else works, there is a stem cell transplant, which is the ultimate treatment for my form of CLL with the p53 mutation. With the p53 mutation, some docs reportedly give you one course of chemotherapy and if you fail go directly to transplant. The problem is that there is somewhere between a 10% and 25% mortality (death) rate with stem cell transplants. You don’t go into them lightly. But, they are said to give “durable remissions” in patients with the p53 mutation. Notice that the word “cure” wasn’t used. It rarely is.
Anyway, I’ve been through “Phase One” of the Arzerra treatments and the short story is that it has worked well, dropping my white count from 80,000 to about 4,000 (normal) in just eight weekly treatments, with minimal side effects. “Phase Two” starts later this month. I’ll leave the details of all this for the next update, since this has gotten long enough. And I hope to have it to you before another six months goes by.
Dave
I read these words in a USA Today recently, while sitting in a chair in the waiting room of the Leukemia Clinic at M. D. Anderson.
“Have you come to the Red Sea place in life,
Where, in spite of all you can do,
There is no way out, there is no way back,
There is no other way but through?”
---Annie Johnson Flint
www.adventureswithleukemia.blogspot.com
