Bass ackwards

I recently read Chaya Venkat’s take on Revlimid at CLL Topics. Is this thalidomide derivative new and promising in chronic lymphocytic leukemia, or new and overhyped given the paltry data we have on it? I’ll leave that for you to judge. 

Revlimid, or lenalidomide, is being touted as a drug for refractory patients, and that is why it is the object of such interest. As Chaya says, and as any big-name CLL doctor will tell you if they’re being honest, there are few drugs available for fludarabine-refractory patients. There is Campath, there are steroids such as HDMP. There is flavopirodol, still in trial at Ohio State. And perhaps HuMax-CD20, when it gets on the market. (There are a few others, basically no more than twinklings in researchers' eyes at this point.) None of these save Campath -- or a risky stem cell transplant -- have yet proven to be powerful players for those who have smoldering bridges behind them and powerful rivers to ford ahead.

Chaya puts it this way:

“It is a pretty well understood fact of life that most cancer drugs will eventually stop working and patients will become refractory to them. Fludarabine is a famous example. For a majority of CLL patients it works like gangbusters the first time around. But as surely as there are taxes to pay each year, patients develop resistance to the drug after a while. The words 'fludarabine refractory' have an ominous sound to them, and rightly so. Patients who no longer respond to fludarabine have far fewer choices.”

In case you doubt what she’s saying, read Dr. John Byrd’s Management of Patients with Fludarabine Refractory CLL, which constitutes part three of the 2004 ASH Education Book.

Take particular note of these comments in the opening paragraph:

“For some patients CLL is an indolent disease that never progresses to require therapy. However, when patients become symptomatic with their CLL, the OS with older therapy is quite short, ranging from a mean of 1.5 to 6 years. . . . At the time of relapse from initial response to fludarabine, 40% can be retreated and will respond again to the same regimen. Data with respect to retreatment with fludarabine and cyclophosphamide or fludarabine-based combinations with rituximab are currently not available. Ultimately, virtually all CLL patients who are treated become fludarabine-refractory.”

So why is the lady on the left -- this image is currently being used by manufacturer Berlex in marketing Fludara -- so happy?

OS is medical shorthand for “overall survival,” something that is “quite short” with older therapy. It may well be longer with newer treatments such as Rituxan-enhanced chemo combinations and Campath. Perhaps it will go from “quite short” to merely “short.” Maybe it will even double -- let’s assume, without any statistical basis but for the sake of argument, that the mean OS of patients using today’s therapies is 3 to 12 years.

I don’t know about you, but I want to live longer than that. For CLL patients in their 40s and 50s with progressing disease, living to the ripe old age of 70 is going to be a challenge. And I bet that even if you’re in your 60s, you’d like to see 80. Things have gotten better for us CLL patients, but they are still not good enough.

Being precipitous at the precipice

Against this backdrop, I think it is fair to say that the treatment of CLL has its own time frame, which has a center point that is as significant in its own way as that of the Christian calendar. Christians divide time into B.C. and A.D., Before Christ and Anno Domini (“In the year of our Lord”). In CLL, there is B.F. and A.F. -- Before Fludarabine and After Fludarabine. Alas, our holiest of drugs provides only a temporary salvation.

So let me pull out my soapbox, upon which I will declaim for a moment about the premature use of fludarabine while dabbing the froth from my mouth: Judging from both personal experience and what I read on patient forums, there are far too many doctors who recommend fludarabine in some combination or another (or even by itself) without giving adequate weight to the consequences. There are patients who can definitely benefit from combination chemoimmunotherapy such as RFC or RF and who cannot afford to wait. But there are many patients who have been hustled into such therapy without really needing it, or without needing it yet.

Usually, but not always, the doctors at fault are well intentioned local hem/oncs who aren’t too familiar with the subtleties of CLL. These subtleties include variations in the disease as diagnosed by FISH test and IgVH mutational status and how treatments work on these subgroups; deciding which among the array of symptoms are important and at what point they demand therapeutic intervention; deciding which therapy is best tailored to cope with those specific symptoms; and thinking down the road about the effect of this treatment on the next and how to preserve as many choices as possible for the future.

Intelligently handling CLL takes effort, but it is not exactly a mystery on par with those known only to the Oracles at Delphi. The information is out there, easily reachable by doctors and patients with a Google toolbar. Everyone should read the NCI guidelines for treatment. And there are two sources of knowledge that are as invaluable as they are available: One is the aforementioned CLL Topics. Chaya, who has a background in science research and education, has done a great deal of thinking about all these issues and has a feel for the lay of the land. The other is Dr. Terry Hamblin’s posts on ACOR and the medical posts on his blog. Terry is forthright and independent-minded and has no vested interest in selling anyone a bill of goods. While one might occasionally disagree with something they say, both are honest brokers who have shed an enormous amount of light on CLL management and care. Any doctor or patient who pleads ignorance when it comes to CLL is not really trying. End soapbox.

The cart and the horse

Which brings us back to where we started. Do you want to add years to your life? Maybe you can do it on the front end, through wise extension of watch and wait. You certainly aren’t going to do it on the back end, when you are fludarabine refractory.

Much research is devoted to finding new drugs, such as Revlimid, for refractory patients. This is necessary and important. (Revlimid is new to CLL but not new; it has been used in myelodysplastic syndrome and multiple myeloma.)

Less emphasis has been placed on what can be done to delay the moment at which patients become refractory in the first place.

This means that improving your OS is partly up to you.

You can extend watch and wait au natural -- that is, by not taking any drugs and simply waiting until things get so very, very bad that you have to. If you expect CLL experts to agree on when, exactly, that point has been reached, forget it. I have written about my own experiences, in which Doctor A would have me in RF therapy and Doctor B would have me watching and waiting. Suffice it to say that I like Doctor B’s approach better. (For patients seeking an expert with a conservative approach to the timing of treatment, I recommend visiting Dr. Hamblin or Dr. Byrd. There are no doubt others, but these are the two I know most about.)

Extending W&W can also be done by using things that may help control disease progression, but at little cost in terms of building disease resistance.

These include the aptly-named chemopreventives, such as EGCG, the green tea polyphenol. It seems to help some people, and it has been in a CLL Topics-sponsored clinical trial at the Mayo Clinic. Hopefully this year, as the ground thaws in Rochester, MN, we will finally hear some results.

There are vaccine trials, such as Genitope’s MyVax, in which early stage patients are given personalized vaccines in an effort to foment an immune response against CLL cells. It’s experimental, of course, but if it works it could become an important tool.

Then there’s the slightly more costly stuff in terms of disease resistance and possible side effects -- single agent Rituxan, for example, perhaps with boosters such as EGCG and fish oil (Chaya’s “RHK” protocol) or Beta-Glucan or steroids. This is what I have been doing -- using immunotherapy to stave off the day when I have no choice but to start chemotherapy. I am not the only one doing this, and none of us know how well or how long it will work.

And that brings me to the larger point here: The world of CLL research is focused on maximizing remissions when treatment time comes and then on finding ways to save the inelegantly-named salvage patients who have relapsed from those very remissions. Little effort has been devoted to extending the time before chemotherapy is needed, before the first step is taken down the slippery slope.

Fortunately, a paradigm shift may (slowly) be in the works.

Early intervention

Why has it taken so long to try to put the horse before the cart?

A big reason, I think, is that researchers haven’t had the tools to work with until now. They didn't know whose disease was likely to progress, or why. And we have only recently come to understand in depth some of the cellular mechanics at work in CLL. You cannot target a therapy unless you know what to target it at.

There are other considerations. Staving off the inevitable may not seem like so worthy a goal when you have patients for whom the sword of Damocles has definitely dropped. Perhaps it is a matter of time and resources, and perhaps there is more glory and money in providing deeper remissions when treatment is needed than there is in the mundane act of merely keeping something from happening.

But thanks to what has been learned about a host of things, especially IgVH mutational status and chromosomal abnormalities as detected by FISH, the idea of risk-based management of CLL is beginning to take hold.

Indeed, there are those experts who wonder if early intervention might not even cure CLL in asymptomatic patients who are likely to have progressing disease. Yes, I said “cure,” and this is how the idea of early chemotherapy enters the picture. Until less invasive approaches like vaccines prove effective, chemo that of late shows improved depth of response may be the likelier route to a cure.

If I could move the clock back to 1996 or whenever it was that I was a Stage 0, asymptomatic patient, and if I knew that RFC plus every other letter in the alphabet might give me even a 25% chance of a cure, I’d try it.

There is a growing consensus today that early intervention may be warranted in 17p-deleted cases, which are known to turn rather quickly aggressive and have the shortest survival. The dangers of chemo may be mitigated by the dangers of letting the worst form of CLL get out of hand. Determining who might benefit from early treatment and what that treatment is -- and the answers probably won’t be the same for every patient -- is a logical next step, fraught as it is with ethical questions.

Dr. Byrd has proposed an early intervention trial, CALGB 10501, in which high-risk (unmutated) patients would be split into two groups: One group would receive FR in the traditional time frame, when symptoms develop. The other would receive it early on, before symptoms arise. There have been some concerns about this in the patient community -- can more harm than good be done to some of these early treated patients? I am not sure what Dr. Byrd regards as adequately “high risk” (is mere unmutated status enough?), or that FR without cyclophosphamide or follow-up Campath is the best method of treatment. (Indeed, there is a similar trial under consideration in the UK that uses Campath alone.)

But answering the general question -- Will early intervention in patients who are likely to have progressing disease lengthen their overall survival or even lead to a cure? -- is important.

As Dr. Hamblin has commented:

“The idea of early treatment studies is that you can now pick out from marker studies those patients that will eventually need treatment. For this group it might be that treatment with curative intent could succeed while the bulk of disease is small, yet is doomed to failure by the time the bulk increases sufficiently for the disease to become symptomatic. It is an hypothesis that should be tested with a clinical trial. . . . The trials should go ahead because we really ought to know the answer. This sort of trial will have an end point of cure, so the sooner they are started the sooner we will know.”

Dr. Byrd indicated in his presentation here that it could take 5 to 10 years to work this out. (He also issued the caution that, outside of a clinical trial, “treatment should not be initiated until symptoms or cytopenias develop from CLL.”)

Until then, we patients are going to be left largely to our own devices.

Green tea, anyone?