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Article Review: Prognosis at Diagnosis


by Chaya Venkat

I would like to review for your reading pleasure the latest article by Dr. Neil Kay, et. al. (Mayo Clinic):

Prognosis at Diagnosis: Integrating Molecular Biologic Insights into Clinical Practice for Patients with CLL. 
Tait Shanafelt, M.D., Susan Geyer, Ph.D. and Neil Kay, M.D.
Blood First Edition Paper - pre-published online October 23, 2003. 

If you are a newly diagnosed CLL patient, and for some strange reason you have taken a vow to read only one technical paper on CLL, this should be the one. Each of you should print this paper out and take it with you to your next meeting with your oncologist / hematologist. Much of the material in this paper has been covered by other papers in the last few years. What makes this paper unique is that it puts it all together in one irrefutable package: the research, the results, the logic, the recommendations. I have no doubt this paper will be one of the most influential papers in CLL, and will be influencing clinical practice for many years to come. Below are some highlights from the paper.

The Problem with Being "Indolent"

Some time ago I used the word "indolent" in describing CLL. Nothing strange in that, it is a word routinely used for describing this disease. But one of our readers pointed out that the word "indolent" seems hardly justified for a subset of CLL patients; for these unfortunate patients the period between diagnosis and therapy is all too short. In their cases the CLL fairly galloped. Most of us are offended when CLL is described as "the good kind of cancer to have" by well meaning if rather inept local oncologists. Perhaps we should include the word "indolent" as well in the list of words that should not be used any more in describing CLL, certainly if it means we get the one-size-fits-all service.

Historical Perspective Updated

Rai and Binet staging of CLL patients has been at the heart of the "Watch & Wait" strategy of treatment. Early stage patients were not treated, since there were no drugs available that could provide more than just palliative help with symptoms. Early intervention with chlorambucil did not increase overall survival, so why bother? It was better to wait until the symptoms got bad enough, then start the chlorambucil. Now we have better choices, but unfortunately the old logic is still applied. Early stage patients, as defined by Rai or Binet staging systems are typically not treated. Recent work has pointed out some of the shortcomings in these staging systems, not the least of which is the reason for anemia and low platelet counts (see article on the need to update the Rai and Binet staging systems). With better record keeping and well documented retrospective studies, it has become clear that not all early stage patients fall in the same prognostic bucket. Some smolder at the starting block, some amble along at a slow clip, yet others seem to sprint to the next stage. It seems intuitively obvious that one size does not fit all, in how these early stage and newly diagnosed patients should be treated.

The paper goes on to discuss each of the clinical and prognostic indicators that have been considered, how well they have stood the test of time as true predictors of patient prognosis, how they relate to each other, and how best to use them in defining subsets of patients with distinct profiles, with clearly defined therapy requirements. Besides the Rai and Binet staging systems, the paper goes on to discuss lymphocyte doubling time (LDT), beta-2 microglobulin (B2M), mutation status of the variable region of immunoglobin heavy chain (IgVH), CD38, FISH (chromosomal analysis to determine the specific genetic aberrations), p53 gene mutation status, serum thymidine kinase levels (TK levels), ZAP-70 expression and the level of expression of angiogenesis markers, such as VEGF.

Each of these parameters, with the exception of serum thymidine kinase, has been discussed in one of our recent articles " What Type of CLL Do You Have?" VEGF and VEGF receptors have been discussed in another article "Do You Like Drinking Green Tea?" (I swear I did not get to see an early draft of Dr. Kay's paper! This is not a case of plagiarism but one of sincere admiration. Much of my admittedly self-taught education in hematology as it pertains to CLL has come from reading expert papers by this and other leading researchers in the field. Nonetheless, I have to admit to some pleasure that I missed only one of the long list of prognostic indicators discussed by Dr. Kay and his co-authors in this pivotal review paper.)

Making Use of the Hard Won Knowledge

All of this is so much jargon and useless gibberish, unless we are able to translate it into a format that helps us and our doctors in making better therapy decisions. We defined three prognostic "buckets" on CLL Topics, and for each bucket we suggested guidelines on how to proceed. The new paradigm would be action plans based on a logical definition of risks and rewards. While our "bucket" approach is sort of by the seat of our pants, this paper goes into the statistical modeling of the variables, sample sizes and database of information needed to do this accurately. If statistics and a whole lot of jargon associated with that fun field is not you bag, not to worry. "Buckets" will do just fine. Last but not least, the paper goes on to spell out the recommended studies that should be done at the time of diagnosis of CLL patients:

Shanafelt, Geyer and Kay - Blood First Edition Paper
(c) 2003 American Society of Hematology


If you are a newly diagnosed CLL patient, and your oncologist or insurance company balks at approving relevant tests to get you a decent fix on your prognosis, just have this paper handy, it might be helpful in getting your point across.

Bottom Line

This paper spells out, clearly and unambiguously, the days of one-size-fits-all approach to therapy decisions for CLL patients are over, or they should be! Watch & Wait until the last bitter moment, followed by take-no-prisoners style chemotherapy, or palliative drugs that do little more than help with the symptoms for a short period of time, these were the standards of the past. With the tools available to us now, we can do a whole lot better than that and base therapy strategy on detailed prognosis at the time of diagnosis:

  • We can be prudent and not over-treat patients lucky enough to have relatively indolent disease.

  • We can try to 'stabilize' such "Bucket A" patients so that they stay longer (indefinitely!) in early stage and not allow their tumor burden to get out of control, by using non-toxic and patient-friendly chemopreventive agents.

  • We can monitor them regularly to catch any untoward "clonal evolution" of their CLL to a more malignant form, so that new treatment strategies can be implemented to match the new threat.

  • For patients with an intermediate risk profile, ("Bucket B") we can come up with smart choices based on monoclonal antibodies, immunomodulators, vaccines, ex-vivo grown armies of killer T-cells (CTL therapy) and other similar low toxicity approaches to bringing down their tumor load, followed by a targeted approach to prolonging the remissions with patient-friendly chemopreventive agents.

  • With lower levels of cancer cells to muck up the rest of the immune system, hopefully we will also reduce the risk of developing collateral autoimmune diseases such as ITP, AIHA in these medium risk category patients.

  • With patients in the high risk ("Bucket C") group, we can avoid the risk of waiting too long, take care of the problem before the bone marrow is too heavily compromised, before the heavy tumor burden translates into other potential complications such as anemia and thrombocytopenia, before the onset of chronic B-symptoms that reduce quality of patients' life, before frequent and hard-to-treat infections mandate hospital stays and run up medical care costs. Implementation of immunotherapy and chemotherapy combinations such as RFC and RF etc., as well as autologous bone marrow transplants, mini-allogeneic bone marrow transplants, donor T-cell infusions and the like are much better tolerated and have better chance of success if they are not used as a last ditch "Hail Mary" effort. Under-treating an aggressive form of CLL with therapy choices that are not likely to give a clean bill of health, or waiting too long to implement therapy with sufficient fire power can be dangerous for these not-so-indolent CLL patients.

If all of this sounds to you like the philosophical underpinnings for our Project Alpha, congratulations, you have just aced the pop-quiz. I am delighted to see this explicit, logical and wonderfully detailed presentation of the state-of-the-art thinking in treating CLL patients. If you wish to read the full details in the original article, contact us at - .

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