This would all be a rather fascinating puzzle if it were not for the fact that it is a life and death matter. I feel like I am playing chess with unknown forces shrouded in fog on the other side of the table. Thanks to prognostic testing, my track record with treatment, and the symptoms I have presented over time, I can see perhaps half the pieces on the board. I never know if my opponent will produce a pawn, or a bishop, or a queen out of the mist.
But I play the game. I have to. Over time I get a little better at it, a little more comfortable -- but never too comfortable -- in my moves.
It seems that for some patients there is a playbook but not for me. Those with truly indolent cases might never need to think much beyond Rituxan or chlorambucil. Those with truly aggressive cases can skip a lot of moves and go right to a disease-nuking regimen followed by a mini-allo stem cell transplant. Those in the middle, like me, have no clear choices.
For the record, I am IgVH unmutated and ZAP-70 positive, both bad indicators. But these are held somewhat in check by a couple of good factors: I am CD 38 negative and have an unknown chromosomal aberration (i.e., a “normal” FISH test result) that appears to be on the less problematic end of the scale. (If all this sounds like gibberish, get thee to CLL Topics and learn what this stuff means. You can’t play the game very well without knowing it.)
According to Dr. Terry Hamblin’s analysis of mongrel patients who are unmutated but who are also CD 38 negative, the median survival for people like me is 15 years. I have learned not to take such things as a death sentence (see my post Riding the Curve). But I do accept that I am in a group that must tread carefully in order to beat the odds.
Making this game more of an, um, “challenge” is the fact that while I was diagnosed in 2003, I am fairly certain that I have had the disease for at least 10 years. Prior to diagnosis, my last CBC had been in 1996. I recall my then-doctor telling me that my white count was a little high, and that it was probably just an infection, but that I should consider have it retested in a month. Being 39 years old, feeling fine and still blessed with illusions of immortality, I sloughed it off and went about my business. I do not recall the count, and the doctor no longer has my records, and like an idiot I didn’t ask for a copy, but I believe it was in the low teens.
That I was diagnosed seven years later at Stage 2, with swollen spleen and lymph nodes and an absolute lymphocyte count of 130,000, is entirely consistent with how one might expect the disease to progress. In 1999, I had a rather dramatic-looking squamous cell skin cancer, and such cancers are more frequent in CLL patients; I had another in 2005, and so I know I am prone to them. Though diagnosed in September 2003 and unaware of the swollen lymph nodes in my neck, once I knew what to look for I began to think back to December 2002, when I had noticed, while shaving, that I was getting a bit “jowly,” which I chalked up to the vagaries of aging. To my mind, the jury of circumstantial evidence points to my having acquired CLL, if “acquired” is the right word, in 1996 or even 1995. I was very young, some might say precocious, and my “watch and wait” came and went without my even noticing it.
That, I believe, was a blessing, because in all likelihood I would have started treatment -- made a big move on the board -- sooner than I actually did. And if I have learned one thing, it is that there is no point in premature treatment. And I would have embarked on this course in the pre-internet era, or at least when very little information was available online. (And this was also the pre-Rituxan-in-CLL-era, and that was the treatment I ultimately chose.)
As a result, I would probably have relied solely on the advice of my oncologist, who would have been the fludarabine-happy and somewhat clueless Dr. Lippencot that I have written about previously. This means that by now I might have been fludarabine-refractory, perhaps having acquired another, more worrisome chromosomal mutation making me resistant to any number of treatments. Not to mention that, since fludarabine severely depresses T-cell function, and T cells surveil against squamous cell cancers, I might have come down with a disfiguring or even fatal aggressive skin cancer. Perhaps I might have gotten it from walking hatless and sunscreen-less over the scenic half-mile path from my home to Lippencot’s office, pausing to dawdle over desert wildflowers or to watch bunnies scurry amid the bushes. In retrospect, I could well have been on my way to landing on the bad end of the mongrel median.
The number of bullets I may have dodged by being ignorant is astounding. But ignorance is no longer a benefit. Now that my CLL is flowering, as it were, knowledge is power.
Twelve thoughts on how to play the game
So what have I learned?
First, there is nothing wrong with being slow and deliberate, no matter how many people (read: doctors) are shouting at me from the sidelines to do something.
Second, the more you know about your CLL, the better. It is tempting to not want to know the results of prognostic tests. But if you want to play the game with any hope of success, if you want to see a few more of the pieces on the board, you have to suck it up and learn your IgVH status, your CD 38, your FISH results, and your ZAP-70 (keeping in mind that the latter is not yet standardized and is still a work in progress). As you learn these things, remember that they are only guides to what might happen, not guarantees. And that they do not provide the complete picture, for there are no doubt some other prognostic indicators hidden in the mist, ones we will only come to know in the future. But they can nonetheless indicate to you that some moves might be better than others. It has now been shown that fludarabine and Rituxan are of little use in patients with the 17p deletion, for example. Campath, not usually the frontline therapy for any other kind of CLL, may be the more logical choice. But if you don’t have the FISH test, and don’t know you have the 17p, your doctor will more than likely steer you toward something involving fludarabine and Rituxan. (And for breaking news on how different groups with different prognostic test results respond to RF, read a review of the latest report by Dr. John Byrd at CLL Topics; knowing your prognostic status and these results might be helpful.)
Third, there are other factors at work besides CLL that might affect treatment choices. In my case, squamous cell cancer is a big issue and tips the scale against using highly immunosuppressive drugs such as fludarabine and Campath. Not that I won’t use them one day, but there will have to be powerful reasons for my doing so, ones that override the skin cancer issue. Autoimmune diseases, such as AIHA or ITP, can also play a role in treatment choices. Being Coombs test positive, I am a candidate for AIHA. Drugs that may trigger it are therefore a concern. Almost every drug used against CLL has some potentially ugly side effects and it is writ large on Page One of Logic for the Compleat Doofus that these should be researched thoroughly before embarking on any treatment. People with heart trouble, for example, may want to think twice about the “H” in CHOP (doxorubicin) and the “M” in FCR+M (mitoxantrone). As we have learned through Chaya Venkat's reporting in the case of the latter, not every clinical trial operator is going to inform you of the full potential of a drug to screw with your system. Please do not assume that your doctor knows, or will tell you, all the possible side effects of a particular treatment. (Google is your friend; use it!) And never forget that the side effects of chemo can, for some people, be worse than the disease itself.
Fourth, learn to differentiate between what is a compelling reason for treatment and what is a not-so-important reason to treat. This is a hard one that I’m still grappling with, and it’s one that many doctors have trouble with as well. You may recall that Dr. Lippencot and her partner felt I needed treatment solely because a lymph node “might cut off” the bile duct to a kidney, which, it turns out, is not a common concern. And we should all know by now that good doctors treat the patient, not the blood count: Doctors who start treatment when the WBC crosses a certain line, such as 100,000, make Lippencot look like a candidate for the Nobel prize in medicine. And let's remember that two blood test results in a row are just that, and only with a third and fourth do we begin to sense a real trend.
Of late I have been dealing with spleen issues. Mine was swollen to 18 cm at diagnosis, reduced to normal after my first course (8 weeks) of Rituxan. It grew back over time and the second course (4 weeks) of Rituxan did little to reduce it. Facing the need for treatment the third time, I pondered adding more toxicity to my white bread Rituxan in the form of prednisone or methylprednisolone. I wondered about low-dose chlorambucil, or perhaps even low-dose fludarabine. My doctor brought up the possibility of R + CVP. And then I wondered about the consequences of just living with a large spleen. Sure, it could get ruptured in a car accident. But so could a lot of things.
I decided to look in the ACOR archives to review other patient experiences. There I found one person with an “enormous” spleen of 14 cm following a doctor’s advice to rush into treatment, while another person with a “mildly swollen” spleen of 16 cm has lived with it for years, an arrangement with which their doctor is entirely comfortable. Some doctors -- the better ones, anyway -- will rely on the NCI Working Group guidelines to determine if treatment is warranted. But even here, there is some wiggle room that requires understanding an individual patient’s case and how a patient’s quality of life is being affected. Take my big spleen (please!): If platelets are normal and there appears to be no undue internal problem being created, so what if the damned thing is more than 6 cm below the costal margin (rib cage), which the NCI defines as the point of no return? The NCI guidelines are valuable and should not be dismissed, but I do not see them as some sort of holy book. They are the consensus of a number of top doctors based on a large number of cases, which brings us to:
Fifth, keep in mind that CLL is idiosyncratic and that all cases, and results, are individual. Take blood counts. Some people function fine with an ALC of 200,000, while others have multiple problems at 50,000. Some patients report severe fatigue, while others, like me, have no sign of it. Let’s look at the NCI guidelines again: If one feels fine and is otherwise functional and is able to clot blood with platelets at 70 -- 30 below the NCI trigger and some 70 below normal -- should one treat? Well, there are some doctors who wait for platelets to drop to 50 or 40 before starting treatment, and I side with their conservative approach. (That’s just my opinion -- worth, as always, exactly what you’re paying for it.) Yes, I believe it warrants heightened watch and wait. But treatment is always the last thing to do in CLL (after all, the disease will inevitably return, and the longer you wait, the more treatments will improve). Another point: Just because a majority of patients respond to Treatment X in a certain way does not mean that you will. You could do better, you could do worse. When you move a treatment piece on the board, you are always taking a risk. You cannot know for sure how your opponent will respond. Once you do know -- and I now have a pretty good idea of the effectiveness of Rituxan in my case -- you can plan your next move accordingly.
Sixth, question the conventional wisdom. Some treatments, especially those promulgated by popular doctors, can gain a bandwagon effect among CLL patients. A lot of patients (and local doctors) have hopped on Dr. Michael Keating’s Texas-sized RFC express, for example. Dr. Hamblin, who often recommends the older and decidedly unsexy drug chlorambucil, makes a compelling case that heavy-duty treatment may not always be warranted. Chaya Venkat, the CLL Topics science writer and patient advocate, is prominent in the school of thought that Rituxan-based immunotherapy may be a good low-toxicity choice for some patients. Again, remember that your personal disease characteristics and individual health factors will play a role that might mitigate for or against a particular course of action. In CLL, one size definitely does not fit all and it can pay to think outside the box.
Seventh, think about the long-term consequences. With every reward there comes a risk. This is a biggie that I revisit over and over again in my posts. If you make a certain move, how might that affect moves you can make in the future? I have had three courses of Rituxan within the past two years and have achieved 23 months of disease control with it. While I did not know my mutational status when I chose this path -- the test was not generally available then -- the new Byrd report informs me that unmutated patients using RF as a frontline therapy can go a median of 31 months before the disease returns. So I am close to meeting and beating that median, and I have avoided the toxicity of that regimen, and not only am I not fludarabine refractory, I am still fludarabine-naive. If and when I use it, I should get a good response from it, which is a far trickier proposition for those who have already used it. (And its synergy with Rituxan should help boost the effectiveness of the monoclonal, since I am obviously not naive to that.)
Here's another example (from which you might gather what my current thinking is about what to do if Rituxan montherapy begins to fail me): It appears that most chlorambucil patients will later respond to a combination therapy such as RF or RFC. The reverse, however, is not true. So using chlorambucil (perhaps in combination with Rituxan) might buy you time. (Then again, for your particular CLL, it may be a waste of time. No one said the game was not maddening!) Another example: if a stem-cell transplant may be in your future, you will want to preserve your opportunity to get one very deep remission, which is what is needed prior to the transplant, and which is a key to success. So if you repeatedly subject yourself to heavy-duty chemotherapy, to the point that nothing works very well when transplant time comes, you have probably shot yourself in something more important than the foot. Finally, keep in mind that chemo-naive patients usually have the best response to treatment, so choose your first treatment wisely.
Eighth, assess the magnitude of your disease and the magnitude of the response. It will not hurt a Stage 0 or 1 patient with decent prognostics to experiment with EGCG (green tea extract) alone as a means of disease control. But if you are at Stage 3, unmutated with the 11q or 17p deletion, wasting time on EGCG alone is time you could be spending on a more effective treatment. I suppose a way to look at it is: Little drugs for little disease, big drugs for big disease, aggressive therapy for aggressive disease. As much as I believe treatment is the last resort and that wanton use of chemotherapy is the biggest problem in CLL, I fully recognize the value of chemo when applied properly at the right time. It is the major weapon without which we could not play the game effectively.
For mongrel patients like me, assessing the magnitude of the disease is an enormous challenge, which is why I had so much material for this post. For the record, I have concluded that my disease is on the good end of the bad side, responsive enough to soft-glove therapy that it can be controlled that way, at least for now. My platelets have been trending gently downward (I am unsure of the cause) but are still normal; my HGB is healthy and shows no sign of going south. I feel fine. Lymph nodes are numerous and have never, to my knowledge, exceeded 3 cm. And the spleen, which had been 10 cm below the costal margin prior to my just-concluded third course of Rituxan, is currently "not palpabale" according to my doctor. (In the end I decided to stick with Rituxan alone again but to go for eight rounds this time instead of four; that -- and perhaps strenuous exercise to get the drug into all the nooks and crannies of the spleen -- might have had something to do with the good result.)Ninth, get your facts straight. “Clinical trial” does not mean “panacea” -- it means “experiment.” OR means “overall response” and CR means “complete response,” and neither may have anything to do with the biggie: OS, or “overall survival.” In other words, one may get a deeper response from Treatment A than from Treatment B, but that doesn’t mean you will ultimately live longer. (This may seem counter-intuitive, but it is sometimes true.) And since most CLL treatment regimens are a work in progress, we simply don’t know if they will ultimately translate into a longer, or significantly longer, OS -- one that might justify the risks associated with their toxicity. (Nor do we know how the track record for single-agent Rituxan will turn out.) That means we are left to make educated guesses. In few other diseases are the choices and timing so tricky. The working title for this post was "The game from hell," and this is an example of why I think the name is appropriate.
Tenth, triple-check everything. Blood labs make mistakes. Doctors get brain fugues. Hell, some patients are even misdiagnosed. And things can evolve: CD 38 can change over time, as can chromosomal abnormalities as detected by FISH test. Last year’s test may not hold true for today. Finally, remember the immortal words of Ernie Hines, the managing editor at a newspaper where I once worked: “You know what happens when you ASSUME something? You make an ASS out of U and ME.” Corny but true. (When the nurse brings the clear bag to the IV pole, I make sure the bag says “Rituxan.” The spirit of Ernie Hines is there, saying, “Do you know how many medical accidents happen every year?”)
Eleventh, before making a big move, consult with others. Now is not the time to get tunnel vision. Get a second or third opinion from a doctor. Talk about your options with fellow patients, or even with a wise friend who may not be an expert on the subject. There are a lot of people out there, in groups such as ACOR and in places such as CLL Topics, who can offer insights and tips. They can’t decide for you, but they can give you some things to think about. Despite your best efforts, you may have missed something that matters. The experiences and insights of others will help you understand the landscape better. The ACOR archives are valuable as well, since you can look up the experiences other patients have had with the same treatment you are considering.
Which brings us to twelve: Follow your own instincts. By that I mean: do not rely on what anyone tells you -- be it Dr. Keating, Dr. Hamblin, Chaya Venkat, or internet bloggers -- as being the immutable truth. Advice, counsel, considered opinions: yes. The word of God: no. The experts often differ (and I am not including myself in that group). You have no choice but to assume the responsibility for making the final decision yourself. So embrace it. Since you have to play the game, play it with all the power and insight that you can. And when making a move in the game, make sure you are ready, that you have your game on, that you’re warmed up and prepared. When you lift your hand to make that move, make sure that it truly feels right. Whatever happens next, however your opponent reacts, you will be at peace with your decision. That, my friends, is invaluable, for I believe your heart has to be in the game to win it.
Testing packages for IgVH mutational status, CD 38, ZAP-70, and FISH are now readily available to patients worldwide at Quest Diagnostics. (UPDATE: As readers will find as they continue forward with the blog, I believe Quest's ZAP-70 test is currently unreliable -- September 22, 2007.)
The NCI working group guidelines are, according to Dr. Hamblin, currently being revised. The soon-to-be-outdated ones are available here as a PDF:
This PDF from 2003, written by Mayo Clinic doctors Tait Shanafelt, Susan Geyer, and Neil Kay is more up to date:
From the just-completed ASH conference, by Dr. Michel Hallek:
Treatment issues for those who are becoming hard to treat, by Dr. John Gribben, from the 2005 ASH conference:
Finally, there is much information at CLL Topics about single-agent Rituxan as the basis for first-line treatment. While not especially popular with the medical establishment -- you will not find it touted in the references above -- it makes a great deal of sense to any number of patients, including myself. This is a perfect example of where I would argue that it may pay to ignore the conventional wisdom.
Site search of CLL Topics under "single agent Rituxan"