Sunday, August 12, 2007

What a little Byrdie tells us

Dr. John Byrd, the CLL expert from Ohio State University in Columbus, had some interesting things to say in a recent telephone interview with the Leukemia and Lymphoma Society.

Byrd is one of my favorite CLL researchers because I think he calls it as he sees it and has good instincts about when and how to treat the disease. I say this not only as a patient who listens to his t
elephone and workshop comments, but also as someone who drove from Arizona to Ohio to see him for a second opinion and who knows several people who are patients of his.

Byrd, like another favorite of mine, Dr. Terry Hamblin, is a treatment conservative. Neither man seems to get caught up in the enthusiasm that prevails in places, namely MD Anderson, where some patients are led to believe that chemotherapy will cure their disease. (I am all for hope, but hope truly grounded in reality; speculative hope is an unkind cut to patients desperately seeking a way out of this box.)

Both Byrd and Hamblin are tethered to Earth by the logic of science, and in the reality of what CLL is, which means knowing how much progress we’ve made, but also knowing how much we don’t know. As Byrd told me, CLL is “a long journey.” It is for patients, and also for those who are working on ways to control and even cure it.

I recently caught up with Byrd’s June comments, which are in the form of a telephone education program called Current Progress in CLL Therapy and Clinical Trials. (There is now so much information available about chronic lymphocytic leukemia on the internet that one can start to suffer from chronic information overload. I am forever backed up in my reading.)

Byrd said some things that I found notable, and which show how thinking is changing and evolving. Reading the full transcript is well worth your while, but I have pulled out some of what I consider to be the highlights, including a surprise or two, here.

Bye-bye BMB (and CT)

The first thing that caught my eye is that the dreaded bone marrow biopsy, bane of many a patient, may be a thing of the past. Like many of you, I was given one, or subject
ed to one, or allowed to have the experience of coping with one, as a routine matter after diagnosis in 2003.

“We’re fortunate in that a variety of new molecular tests have come forward that really trump any advantage to the bone marrow biopsy showing useful information,” Byrd says.“ For most patients who come to see me initially with CLL, unless they have low blood counts or another reason that I would do the bone marrow biopsy, say I suspect an infection, generally we do not do a bone marrow biopsy at Ohio State. Most of the other CLL centers are moving towards this. Actually, the new NCI guidelines that will be coming forward likely within the next year or two are not going to advocate doing a bone marrow at diagnosis unless there’s another question to answer.”

I was also give
n a CT scan, and was threatened with having a CT scan monthly until I agreed to my first hem/onc’s demand that I undergo single-agent fludarabine. Hmm, monthly CT scans or finding a new doctor -- what to do, what to do . . . it was an easy choice. But I still know a lot of patients whose doctors insist on using the CT scan as a tool for routine tracking of the disease. Not Dr. Byrd:

“There may be an advantage in the future for CT scans in predicting how CLL is going to behave, but right now that’s really not established and it’s not a recommended test,” he said.

Prognostic tests and treatment time frames

How do you know how your CLL will behave? Byrd gave an overview of the prognostic tests he recommends, those t
hings that trump the BMB, including FISH and IgVH mutational status. Much of this should be familiar to patients by now (see my sidebar at the right of this page, CLL Prognostics and Planning.)

What Byrd added of note, I thought, was an indication of the time frame that accompanies these test results.
If your FISH test shows a 17p or 11q deletion, Byrd says “there is a 50% chance that at one year you’ll go on to require therapy. There is a very good chance that by three to five years virtually all the patients in that group will have to
go on to therapy.”

As to IgVH mutational status, Byrd points out: “IgVH-unmutated CLL patients all eventually requi
re therapy and the halfway point, where 50% of patients go on to therapy of 100, is about three years.”

So, as you can see, knowing those two pieces
of information can give you an excellent idea of if and when you may need treatment. Unless you prefer the life of the ostrich, there is no excuse for not getting these tests done. (I should add here that Byrd finds value in the ZAP-70 test but cautions that it is “very unreliable” when done at commercial labs. My own experience, in which Quest Diagnostics had me as both positive and negative, bears this out.)

In summing up, Byrd says, “There are three things we do when we see somebody at Ohio State initially for their CLL to predict how their disease could behave in addition to an exam: clinical staging, looking at the red cells and the platelet counts; the interphase cytogenetics, or FISH; and the immunoglobulin gene mutational status. That helps pick patients whose disease is going to behave in a more aggressive manner versus a less aggres
sive manner.”

When to start treatment

Byrd give
s an excellent rundown on the question of when to treat, including whether early intervention might be warranted in aggressive cases, as well as some of the complications that can accompany progressing disease. This alone is worth your reading the full transcript, but I will mention one highlight here.

As to the timing of treatment, he says (italics mine):

“Often patients are asymptomatic when they’re treated. They have
big lymph nodes or lymph nodes that are increasing, but they’re not bothering the patient. Their white count is going up, but they don’t have any other symptoms of the disease. And therapy i
s recommended too early. I make that point because if you’re not having any symptoms from the CLL and you start treatment, treatment is likely going to make you symptomatic. We tend to be very conservative when we start treatment.”

A man after my
own heart -- for the longer I deal with CLL, the more I think there is wisdom in the words of the American commander William Prescott, who said at the Battle of Bunker Hill (with apologies to my British friends): Don’t fire until you see the whites of their eyes.

Single-agent Rituxan v. fludarabine

I have been milking the single-agent Rituxan cow for nearly four years, to the point that it can barely moo anymore. One of the listeners asked Byrd about Rituxan maintenance, which I know a good d
eal about from experience. Here is his response:

there has not been a randomized study of maintenance rituximab in CLL after reduction of the CLL with chemotherapy. There is a study that I understand is going to be starting in Eastern Europe to look at this. The only data that exists for rituximab being given repetitively over a long period of time is a study that was done by Dr. Haynesworth (sic) in Tennessee. That study showed that giving four weekly doses of rituximab every six months for a period of two years resulted in a remission similar to that achieved by fludarabine.

“So my take on rituximab maintenance by itself for CLL is that it may add a little bit, but probably the biggest advantage for treating CLL is going to be giving rituximab in combination with other
therapies. As a single agent it’s about as good as fludarabine as a single agent.”

Ahem. Did you
notice that last comment? As a single agent, Rituxan is “about as good” as fludarabine?

Now there may be some who, in terms of the statistics about CRs and PRs and the like, will take issue with that statement. But I think Byrd is talking about the effect on balance, over time, on a person’s CLL as part of that long journey.

I wish I could bring this comment to my long-fired first hem/onc, Dr. Lippencot, who refused to hear the word “Rituxan” and who insisted on fludarabine, fludarabine, and more fludarabine. But
if any of you are still out there, visiting local hem/oncs who have been hiding under a rock and who insist that you be treated with single-agent fludarabine, take notice: In the opinion of one of the world’s leading experts, it is no better than single-agent Rituxan.

Byrd says, as do all the experts and accurately so, that Rituxan works better in combination therapy than alone. Byrd also makes the point in his interview that your first treatment choice is your most important because it can give you the longest remission. Does this mean you should always go with the therapy that gives you the biggest bang?

That would be an interesting question to ask the doctor the next time he does an interview.

Personally, I think it
depends on the type of CLL you have and how it is presenting itself. Your case may merit one of the combination therapies such as RF or RFC. But perhaps a gentler hand will suffice, and in those cases there is no reason not to consider using Rituxan alone, maybe with a pulse of steroids to reduce nodes: the question in CLL is not always what works best, but what, tailored to your situation, will work well enough while preserving options for the future. It was none other than Dr. Byrd who counseled me to save RFC for transplant preparation. CLL is a long journey, remember.


Anonymous said...

I wasn't given a bone marrow biopsy at diagnosis. I did have a lymph node biopsy, from whence the diagnosis came. I wonder if it all that common now, anyway.

Most BMBs are done in anticipation of, or after, treatment. I doubt that has changed.

It is also important to know that too much is unknown about CLL to make any hard and fast rules about when to treat, how to treat, and what to expect from treatment. Dr. Byrd's thoughts are good ones, and it is probably not NOW a good idea to treat unless absolutely necessary (what other cancer is like that, huh?). However, neither Dr. Byrd nor anyone else has a cure for CLL, knows the 'gold standard' of care, or believes that he, and he alone, understands the disease best.

We are just too early in the research efforts into CLL. If you liken these efforts to the Wright Brothers to Neil Armstrong, we're probably deep into the bi-plane era; certainly no farther than Lindberg.

Jenny Lou said...

David, I also enjoyed reading Byrd's comments on CLL. It still frustrates me to know that we really don't know that much about how treatment will affect us down the road. MDAnderson only does BMB now in trials. I think that is protocol for all trials. One before treatment, one at 3 months and one after treatment. Trust me, 3 is enough! Tom is always overjoyed that Keating is not interested in another BMB for him--unless of course, he goes through another trial. Keating says that a flow tells him what he needs to know. I do have a question that I wondered when I read the Byrd interview. He and Keating have both said that they look at the RBC. Is that for the counts that are low and staying low? And, does that show the marrow is on overload or what? Or is he mainly talking about anemia?

David Arenson said...

Jenny Lou, I think when the docs look at the red counts they are looking for signs of a decline in red cell production and resulting anemia, which puts you in Stage III (as opposed to an autoimmune cause, such as AIHA, which can happen at any stage and which does not result from marrow impaction). Platelets tanking due to marrow impaction (as opposed to ITP) puts you in Stage IV.

One of the reasons I have avoided hard chemo is that my marrow is still functioning and my platelets and red counts (when I am not hemolyzing due to AIHA) are in the normal ranges, and therefore well above the NCI triggers for treatment (hemoglobin of 10 and platelets of less than 100k).

The first commenter makes good points that I basically agree with. I hope we're at the Lindbergh level, though sometimes I feel like we're at the Roswell UFO crash point.

I would caution that Dr. Keating thinks he might well have a cure for CLL in RFC. He has said as much on his website, CLL Global, and in reports of conversations with patients. He does seem to be a bit of an exception to the humility rule. Is he merely enthusiastic, or is he reckless? You be the judge.

~ chris said...

As far as treatment is concerned, I would take the path that does the least amount of damage to the immune system, even if the CLL effect is not as good as other more cytotoxic treatments.

Time and time again I see CLL patients treated and they start down the slippery slope from which there is no return, because their immune system are compromised to a point that secondary infections can enter and take over. This starts a vicious circle of infection and treatment infection and treatment ending in death.

My mantra has become..."protect your immune system at all costs."

Anonymous said...

Hi David,
Great timely post, thanks.
Do you know the reliabilty of the IgVH test?

David Arenson said...

Carlin, I believe the IGVH test is considered to be reliable at reputable commercial labs as well as research centers. It's been around for several years now and is not like ZAP-70, which is still a work in progress.

Chris makes a good point. Protecting the immune system is a second reason why I have avoided "real" chemo so far.

With CLL and immunity, it does seem in progressing cases that if the chemo won't get you, the CLL eventually will. There may come a point of diminishing returns for me -- the immune system I am protecting may be so broke that it needs a transplant to fix it. For example, as time has gone on my immunoglobulins have tanked and I am now subject more easily to infection than I used to be, so this can and does happen in the natural course of the disease. But I do buy the argument that, if you can, it is better to limp along with a reasonably functional immune system than to gum it up further with T-cell-depleting therapy. This is assuming there is no major reason for treatment -- for example, marrow impaction resulting in anemia and thrombocytopenia.

I think a larger point Byrd is getting at but doesn't come out and address is quality of life -- even if your count is high and nodes are growing, if you feel pretty good and have a pretty normal life, there is no point in risking the downsides of treatment.

Anonymous said...

Thanks David.

Kathy said...

Hi David,
Thank you for such an informative site. My husband, age 57, was just diagnosed with CLL in April, 2008. We are very new to CLL-world, but have spent alot of time on the internet and have been quite lucky to get an appointment with an associate of Dr. Byrd's at OSU. Long story short, my husband is basically asymptomatic, 1-2 small lymph nodes in his neck, but testing results at OSU (FISH showed 13q positive and BMP showed unmutated cell status) placed him in the high risk group. Dr. Byrd is currently running a clinical trial--CALGB 10501--for asymptomatic, high risk CLL patients who have never been treated. Three arms to the study: Arm A-begin standard FR treatment now, Arm B-begin standard FR treatment when symptoms worsen, Arm C-mutated status, begin treatment when symptoms worse. My husband will be randomized, due to his unmutated status to either Arm A or B. If he is placed in Arm A, FR therapy will begin in Sept/Oct. We are so new to all of this, and I do understand the value of clinical trials in helping all of us get to the bottom of this disease. And, while we were so excited to be able to be seen at OSU and hoping that there would be something that we "could DO," now that there is something we can do, we are struggling with worrying about starting treatment too soon, especially after reading your comments from Dr. Byrd. We welcome the comments of others who have been around this block for awhile. We are faithful readers of clltopics and get much of our info there. Thank you for any thoughts.

David Arenson said...


The trial your husband is in is one of the most important in CLL, in my opinion. Answering the question of whether risk-adapted early intervention increases survival in CLL patients will be of great use to those who have to make treatment decisions in the future.

Early intervention for an unmutated (bad prognostic) but 13q (good prognostic) patient is definitely experimental. The traditional view is to watch and wait. Those joining the trial are taking a risk, but it could cut both ways. (Early intervention could turn out to be a really good thing.) But, as of now, it is generally seen to be beneficial only in cases of some unmutated, 17p-deleted patients, those with especially aggressive disease.

I believe it has been shown that early treatment with chlorambucil did not extend overall survival (read treatment overview article by Dr. Andrew Pettitt at UK CLL Support Association -- link at right).

As Pettitt points out, and as I think is the situation here, patient preference is often paramount when there is no clear course of action. So if you and your husband feel like you want to be pioneers after all you have read, that is one thing. Perhaps it fits your outlook and personality. If you are doing this to "do something" because you feel a little panicked by his diagnosis, that is another. (You can also try EGCG if you want to do something other than watch and wait, and it has very little downside.)

My advice is always to get in touch with your intuition, your gut feelings, and to go with that.

And also to remember that, as Dr. Byrd told me, CLL is a long journey. There is seldom a reason to jump into something without giving it adequate time to mull over.

Al the best to you,


Kathy said...

Thank you David, for your insight and your thoughts. We were not aware of Dr. Pettitt's research and will certainly follow up on that. We truly appreciate the experiences of those that have been on the journey.