Monday, January 01, 2007

Ten things I’ve learned about CLL

Here is a list of some hopefully useful and occasionally iconoclastic things that I have concluded about chronic lymphocytic leukemia. These are my impressions; your mileage may vary.

  1. WBC is overemphasized by patients and local doctors. A CBC is the easiest way to measure the amount of CLL in the blood, but it doesn’t tell the whole story. Unless your absolute lymphocyte count (ALC) doubles in less than six months, and over the course of at least three tests, the number is not especially relevant. A CBC doesn’t measure disease progression in the lymph nodes, spleen, or marrow. CLL is heterogeneous, meaning it doesn’t follow the same rules in everyone: One patient can have a low lymphocyte count and huge nodes or incipient marrow failure, while another can have a high count and not much else going on. Hemoglobin and platelet counts are as useful as the lymphocyte count when trying to gauge disease progression and/or complications. Relying solely on the generic white blood count -- or, more appropriately, the ALC -- is a mistake. Yet this mistake is made all the time, and the planet is apparently rife with doctors who think that when your WBC or ALC reaches a magic number -- often 100,000 -- it is time to treat. There is a mantra to remember: Treat the patient, not the numbers.
  2. You’re not as healthy as you look. It is easy to assume at diagnosis, when most of us feel healthy, that not much will change. But immunity is degraded in patients with progressing CLL. When you have your first post-diagnosis cold and your lymph nodes swell, you’ll have tangible evidence that something is wrong. As your disease progresses, immunoglobulins will drop and so will resistance to infection. CLL cells can compromise the effectiveness of T cells, and this can lead to squamous cell skin cancers as well as infections. Add the side effects of heavy-duty treatment to this equation and your body can be left at the mercy of almost every bug out there. CLL doesn’t kill patients directly; infections as a result of reduced immunity do, the most common one being pneumonia. Prudent measures -- washing your hands frequently, avoiding sick people, wearing a hat and sunscreen -- should not be scoffed at. You have to help yourself stay well; what you once took for granted is now something you have to work at. So get in touch with your inner Adrian Monk (well, at least a little). You don’t have to live in a bubble -- but avoid unnecessary risks.
  3. Chemotherapy costs you. And I don’t mean financially, though it may do that, too. Chemo won’t cure you. It will knock the disease back -- perhaps a little, perhaps a lot. But it comes with a price: Risking immune suppression that leaves you as fit as an AIDS patient is bad enough; developing disease resistance to drugs and giving rise to aggressive, 17p-deleted CLL clones are tragic consequences. Whether your hair falls out or not should be the least of your worries. On some level, using chemo is robbing Peter to pay Paul. That is why it should not be used until there really is no other alternative. This is especially true of fludarabine, which is the bulwark of CLL therapy in the US, and which has been found to be the source of more and more nasty problems as time has gone on. . . . Now don’t get me wrong: Chemo can add years to our lives. It is better than the alternative. When the disease gets to a certain point, we have no choice. The more the disease screws up the body, the greater the risk we need to take to control it. But chemo is not a panacea. It is a necessary evil -- and I use that phrase carefully and intentionally.
  4. 4 + 1 = 5 and so does 3 + 2. A new paper points out the importance of second-line therapy in overall survival in CLL. Why are patients who start with chlorambucil (CB) living as long or longer than those starting with fludarabine? CB users respond better the second time they are treated because they develop less disease resistance as a result of their first treatment. So the math is simple: Get a big bang at the start and a small bang the second time = 5. A less stellar response the first time and a comparatively larger one the second also = 5, maybe even 6. The question is, is there a way to stagger treatments so that you reach 7 or more? This is what I’m trying to do with single-agent Rituxan. Wish me luck.
  5. Cluelessness is the rule rather than the exception. In a disease where the cause has not been found, and about which the experts disagree (sometimes vehemently), and in which there are no long-term survival studies of the most popular therapies, and which is heterogeneous and quirky to boot, it’s all a guessing game. If there was one obvious approach when watch and wait ends, one consensus choice for treatment, then we’d all be doing it. But there’s not. For Type A personalities who like everything logical and organized, coping with CLL is especially nightmarish. There is an incredible amount of guessing involved, and that starts at the top. Four big-name doctors have now seen my charts; each one had a different suggestion as to what I should do. My experience is not uncommon. . . . Still, there are some tools you can use so that your guesses are educated: It is becoming increasingly clear that knowing your IgVH mutational status, FISH, and CD 38 test results can offer a pretty good idea of what you’re dealing with. (Forget ZAP-70 as done by commercial labs -- until they work out the kinks, the test isn't worth much unless it is conducted at a major research institution.) So have your tests done, consult the best white-coated prognosticators you can find, filter the information through your own intuition, and spin the Wheel of Fortune.
  6. Your hem/onc is a prognostic factor. Tests are not the only prognostic factors. The quality of your local doctor is a big one. A good hem/onc, especially one that will work with a CLL expert, may mean a longer life for you. A bad one can take years off your life by prescribing treatment too soon, and by suggesting a treatment that may be a bad choice. Had I followed my first hem/onc’s advice, I would probably be fludarabine-refractory by now, with little to show for it. Dodging well-intentioned bullets from local docs can become a full-time job. But this is one prognostic factor that you can control, thankfully.
  7. There is one kind of CLL to avoid like the plague and any of us can get it. I am talking about CLL in which the clone with the 17p (aka p53) deletion predominates. It is aggressive, resistant to most treatments, and will require a transplant if you are to survive. Dithering around with softball therapies like single-agent Rituxan will not be of much help (I know this is tempting and I support this approach in many cases, but if I developed 17p-deleted CLL I would accept the inevitability of a transplant and bite the bullet, chemo-wise, to give it the best chance of success). Some patients, usually IgVH unmutated ones, will develop this deletion through no fault of their own. But many will develop it as a result of chemotherapy that kills off lesser CLL clones and leaves the 17p-deleted with your body to itself. These therapies include fludarabine and the alkalytors (chlorambucil, cyclophosphamide). There is no guarantee that a given course of one of these drugs will cause this to happen, but you cannot use them without risking it. Chancing 17p raises the bar enormously when it comes to deciding on treatment, as far as I am concerned, and I think this risk is underemphasized by doctors and in patient considerations that I see on the internet.
  8. Santa moves slowly. There are lots of promising ideas for treating CLL. Until they are tried, tested, and approved, they are no more useful to you than unicorns. The treatment toolbox is the one in front of you today (unless you qualify for a clinical trial, and keep in mind that trials do not guarantee success.) New items may appear in the toolbox one day soon, especially those in Phase III trials that show good results and have fast-track status from the FDA. But theories won’t relieve your symptoms. If you can hold out, do it. But expect the wait to be longer than you want, or expect.
  9. CLL is not the world. Life goes on. Bunnies hop, the sun rises, flowers bloom. Pay attention to those things, and to those you love. They have their own journeys, their own needs, even their own health issues. You can feel better by focusing on others. Absorb your CLL experience into the larger context of your life, not the other way around.
  10. Statistics are general but you are an individual. There are always people who do better than the bell curve, and those who do worse. Some get lucky, others are unlucky, Some work with good doctors, educate themselves, and make some good guesses. Others follow bad advice, stick their heads in the sand, and hope for the best. Neither approach comes with a guarantee of success or failure, but it can’t hurt to stack the odds in your favor as best you can. On patient forums I see this question asked: “How long do I have to live?” Well, to paraphrase John F. Kennedy: “Ask not how long you have to live. Ask how you can help yourself to live longer.”

In the near future, I’ll provide a list of suggestions for how you may be able to do that.

7 comments:

Anonymous said...

A few observations:

'You're not as healthy as you look.' I'd add, and as well as you feel. I felt fine up until the time of treatment because of severely compromised bone marrow. I felt perfectly fine. (During treatment, I felt much worse.)

You don't have to be obsessive about washing your hands, avoiding salads and the like. Just display some commonsense awareness, promptly put bandaids on wounds, be scruptulous about food safety, and avoid infected people.

'Chemo won't cure you.' Probably, but long-term remissions have been reported in FCR, perhaps in other chemo regimes.

'For type A personalities, coping with CLL is nightmarish.' I don't think this is really the case, and it is beginning to become clear that some subgroups of CLL respond better to some treatments than others. Testing the patient for responsiveness to drugs as is currently done in at least two labs, is increasingly interesting to researchers.

I had little trouble deciding on my treatment.

'Forget ZAP-70.' Now hold on here! ZAP-70 is a powerful prognostic indicator, and several labs such as Kipps' in San Diego and Hamblin's in the UK give good, consistant results. I believe Hamblin even offers to test blood from as far away as the US for ZAP-70.

I agree that commercial labs are not to be relied on, and thus are a waste of money.

'Your hematologist is a prognostic factor.' What??? I'd say that your survival depends at least somewhat on your doctor, but it's not a prognostic factor.

As you've said above, there is no agreement on the best treatment for CLL even among CLL experts. The best results are obvious only after years of running trials.

Sadly, the author is correct in noting that more effective treatments, and cures, are farther away than you think.

Anonymous said...

Very well stated David!

It is imperative for a CLLer to learn as much as possible about their own form of CLL and keep their own records. Staying abreast of drugs that work best for certain sets of symptoms; and most of all, be willing to take responsibility to make a final decision on any treatment.

Remember doctors "practice" medicine!

Although there are a number of pledges and oath's taken by doctors (depending on where they go and what kind of degree), most of them contain something to this effect:

"I will continue with diligence to keep abreast of advances in medicine."

and,

"I will seek the counsel of particularly skilled physicians where indicated for the benefit of my patient."

If your doctor isn't a CLL specialist, and isn't willing to work with one - find one that will!

Great blog David!
Denise

Jenny Lou said...

Another fantastic entry, David. The WBC is my favorite. It should be faxed to every oncologist. Good work.

David Arenson said...

Thanks, all.

Just to clarify, my criticism of ZAP-70 is related to the quality of the tests done at commercial labs, which seems to be where most people are having them done. Conducted somewhere like UCSD, for example, the test can be helpful. I think we still don't have a clear picture of its exact significance, though -- of all the common prognostic tests, it's the one with the most question marks hanging over it still.

My "your hem/onc is a prognostic factor" line involves a little bit of literary license. But I stand by the basic idea. Results of your mutational status and FISH tests don't mean much when your doc charts a bad course of action afterwards.

Long-term remissions have been reported in FCR, as have short-term disappointing remissions of lesser quality, as well as treatment resistant relapses.

When we have to use chemo, it's nice to know that things have improved to the point that our lives can be extended many years through better therapy and sensible staggering of treatments. But because of disease resistance that builds as treatments are used, chemo has an inevitable downward slope to it. We can hope that new therapies will level that slope a bit but, as I said, this seems to take an awful long time to happen. HuMax and perhaps flavopirodol seem to be the best things that are really happening, and there is talk about revlimid, its value a little unclear at the moment. None is a panacea, all may be helpful.

Anonymous said...

Note your comments.

I'd still disagree with your assessment of ZAP-70. Dr. Hamblin explained the conundrum well when he recently detailed the difference in methods used in determining the level in the CLL patient.

However, there seems to be little doubt that ZAP-70 is a vaild prognositic indicator, closely (but not perfectly) linked to mutational status. I could literally cite dozens of papers that suggest that fact.

And it also seems clear now that ZAP-70 itself is a signaling molecule that may help drive CLL cell proliferation. See the 9-26-04 New England Journal of Medicine or the June 2006 European Journal of Haematology as well as many other places.

Yes, the role of ZAP-70 in the pathogenesis of CLL is not clearly determined as of now, but it is certainly not a factor that leads to an improved outlook for CLL, and I'd argue that it remains a negative prognostic indicator.

Atilla

David Arenson said...

Atilla,

I agree that ZAP-70 has significance, but I also agree with Dr. Hamblin, who posted to ACOR two weeks ago:

"I do not regard ZAP-70 as an assay that can be relied upon yet. I should ignore it."

My point is that patients are better off with IgVH mutational status, FISH, and CD 38 as prognostic tests at this point -- there is less mystery surrounding their possible meaning, and standards for those tests have been worked out, whereas ZAP-70 is still a work in progress. It may be a better bet a couple of years down the line.

Anonymous said...

Thank you. as recently diagnosed, I appreciate any information I can get.