Case Studies

You Are the Doctor

Date: March 16, 2003

by Chaya Venkat

How Therapy Choices Are Made

This discussion is based on an excellent article from the Moffit Cancer Center: Clinical Reasoning in Oncology - A Young Man with Lymphocytosis.

This is the kind of "patient history" that really helps us in understanding how therapy options are identified and how oncologists make their decisions with reference to individual patients.

If you want to take a look through the eyes of your oncologist, this is a must read article. 

The article is dated 1999, not that long ago, certainly within the time frame when many of our members were first diagnosed. It is interesting to note how much the therapy landscape has changed even in these few short years. Or has it? 

OK, folks: home work assignment. Please do try and read this article, so you can follow the discussion below and have a chance to come to your own conclusions. You won't be able to follow the issues or the debate unless you read the article first.

For A Change, You Get To Be the Expert Oncologist

I am sure you will agree that the Moffit Center article is pretty readable and interesting.

To recap, here is the scenario. For a change, your role is that of the expert oncologist, making life or death decisions for your patients. The poor guy in the Moffitt center article died after a series of therapy choices that were by all means reasonable choices for that day and age, but they just did not work well for him. Let us assume you have a patient today, with a history just like that other guy in the article. Just for laughs, let us give our patient a name, Joe Q. Samurai, and assume that unlike the patient described in the Moffitt article, he walked into your world famous oncology / hematology consultation room just this morning. His GP recommended that he consult with you, because you are the best of the best, and you will take good care of him. Let's see if you can do better for your patient than that poor fellow in the Moffitt center article, with better information and more therapy choices up your sleeve. Here is the case history of Mr. Samurai, as provided by the GP: 

"A 45-year-old man with persistent lymphocytosis that was noted during a routine annual examination is hereby referred for hematologic evaluation. Laboratory studies yielded the following values: white blood cell (WBC) count, 18,200/mm3 with 81% lymphocytes, 16% neutrophils, 2% monocytes, and 1% basophils; hemoglobin level, 14.5 g/dL; hematocrit, 42.7%; mean corpuscular volume (mm3), 86.8; red cell distribution width, 12.8; and platelet count, 245,000/mm3. Peripheral smear showed normal red blood cell morphology with predominant, small, round lymphocytes. The patient is otherwise in apparent good health. Three years earlier, he had a normal complete blood count. Physical examination and routine laboratory test results were normal."

(You will notice the stuff in quotes is identical to the description in the Moffitt article. I told you your patient has an uncanny resemblance to the Moffitt center article patient). 

Since this is today and not 1999 (or earlier) when the real Moffitt patient walked in the door, you order a bunch of new tests, just to get a good handle on Joe's prognosis. You order full quantitative flow cytometry, with special emphasis on CD20, CD52, CD38 and CD23. Also the usual Beta-2-microglobulin (B2M). You know from having read recent articles in trade journals that monoclonals like Rituxan and Campath are likely to play a role in this patient's life, so you might as well know how strong his CD20 and CD52 expressions are.

You also know that many leading CLL experts feel that CD38 is a good prognostic indicator and while you would have liked to investigate the IgVH gene mutation status and run a FISH analysis for chromosomal aberrations, your local lab cannot do these sophisticated tests. So you resign yourself to just getting a good read on the percentage of CLL cells (CD19 and CD5 positive cells) that are also CD38 positive. After all, your buddy Rajendra Damle was telling you just last year at the ASH conference when you had dinner with him that there is a good chance CD38 expression and IgVH gene mutation status are linked in some fashion and that one predicts the other, to some degree. As for the CD23, now that is a simple one to look for. It is after all the B-cell activation marker and gives a good fix on how fast the B-cells are likely to proliferate in the future. 

Just on the off-chance that mutual professional courtesy pays off, you send Mr. Samurai's samples off to the UK, to see if Terry Hamblin will help out with the FISH and IgVH gene mutation status studies. May be if the case is interesting enough, you and Terry can author a joint paper later on the case. 
It takes about 2 weeks to get all the results back. Good old Terry obliges with the fancy stuff. Your super efficient assistant compiles all the data for your easy reference:  

Joe has an appointment to see you tomorrow, he has been sitting on pins and needles while you were waiting to get all the test results. He still has no B-symptoms, but he is having trouble sleeping, binging out on the late night ice-cream and potato chips to calm his nerves, and his new year resolution to go to the gym 3 times a week is long forgotten. He is coming in with his wife. She is the one with the need to know all the gory details. Joe's GP has warned you ahead of time, the wife thinks she is an expert because she has been surfing the web for a couple of months, looking up CLL websites. 

Doctor, What Do You Recommend?

Hope you put down your conclusions and recommendations on a piece of paper. You can then go back to see how you dealt with this case after you finish reading this article.

… and My Opinion?

OK, my turn to play doctor.

I would be inclined to treat this patient sooner rather than later, based on his bone marrow cellularity, unmutated IgVH gene status, middling CD38 levels on CLL cells, and high CD23, B2M. All of these are indications of a poor prognosis. 

A little background about bone marrow cellularity: babies use all of the bone marrow available to them, i.e., cellularity is 100%, because new cells are being made at such a rapid rate, the full manufacturing capacity of the factory is needed. As we get older, and the demand for new cells becomes less, much of the bone marrow becomes inactive, and this process increases with age. This inactive portion becomes filled with fat deposits. The cellular part, the part that is actively making new cells becomes smaller as we get older. A rough rule of thumb is that in a normal person the cellularity is 100 minus your age in years. For our 45 year old patient, a marrow cellularity of 55% would be normal. 90% cellularity means his bone marrow is already struggling quite a bit in making the necessary and vital cell lines, and is able to manage only by opening up previously mothballed inactive portions of the factory. There is obviously a limit to how far this strategy will work, when the cellularity is 100%, there is no place else to go, the bone marrow hits a wall and the cell production will not keep up with demand. This is why so many of us see our blood counts look pretty OK for long periods of watch and wait, in terms of red blood cells, platelets etc, then suddenly fall off of the cliff. Basically, during the period of w&w, the bone marrow is gradually becoming more and more cellular, opening up the reserve production capacity to meet demands, because the part that is functioning is gradually becoming clogged with CLL cells and not able to function as efficiently as before. Once most of the reserve capacity is already in play, and the efficiency decreases further as CLL cells gum up the works, the CBC counts of the vital cell lines start dropping quickly. In previous paradigms, this was the point at which treatment is initiated, after your bone marrow has been backed into a corner, so to speak, and the reducing numbers of red blood cells and hemoglobin trigger the dreaded B-symptoms of fatigue, etc.  

We have a few more indications on Mr. Samurai since he walked into your office today, as opposed to 1999 or earlier when his counterpart saw the Moffitt center experts. His IgVH status of non-mutated, plus B2M of 2.4 suggests he is not going to be a long term smolderer. With his high bone marrow involvement, the high CD23 level of 92% is quite troubling, since CD23 is a marker for B-cell proliferation. It suggests that what is left of the slack of his bone marrow capacity may be sopped up pretty quickly. The percentage of his cells that are CD38 positive is sort of in the middle, at 22%. This is not a candidate for any extended period of watch & wait, in the opinion of this "expert". Since the original pivotal article by Damle, et al., a number of authors have considered the prognostic value of CD38 expression on CLL cells. Damle has used a cut-off of 30% as the level at which the patient is classified as CD38 positive or negative. More recent articles have used a cut off of 20%, as in the abstract below, or even lower, as being better definition of prognosis. It is for this reason that I chose to call the 22% CD38 positivity as "middling"; not exactly a clean bill of health on this indicator, not quite the end of the world either. Sort of middling. 

What therapy is best for him? Lucky for Mr. Samurai, his CD20 expression is pretty good, at 88%, even though the intensity is only 1+ (dim). His CD52 is higher, at 92% and 2+ intensity, but my personal preference is to defer Campath until later stages, mainly because of its immunosuppressive nature. My first bet would be to try Rituxan for this patient. I might want to include an injection of GM-CSF to improve his immune system effector cells (granulocytes, macrophages) a couple of days ahead of administering the Rituxan each week. I would try the Rituxan once a week, for four weeks at standard dose of 375 mg/m2, evaluate the patient again a couple of weeks after the last Rituxan infusion. If the response is there, but not quite as much as I would like to see, I might add on another 4 weeks of Rituxan.  

But before I do any of this, I would sit down with Mr. Samurai and his internet-savvy wife and discuss his personal contribution to this battle in winning back his health. I would point out that good nutrition and exercise have a tremendous effect on his ability to deal with the disease, not to mention the emotional stress of fighting cancer. I would welcome his wife's proactive tendencies in learning about this disease, have some literature for her to read, some pointers on where she can learn more about prognostic indicators, etc. Perhaps I would give her the URL to CLL Topics. Patients and their families are able to deal with the stress of life threatening diseases like cancer when they feel there is something that they can do to contribute, when they are actively engaged in the process of the fight, not just passive and helpless victims. I am always amazed how many doctors have forgotten to treat the whole patient, instead they just treat the disease. Mr. Samurai and his wife are living, thinking human beings. Getting them actively involved in the management of the disease that is devastating their lives can only benefit the situation. As patients we are only too aware when doctors do not think about doing this. Yet, of the few people who responded to this little role play on CLL Topics, not one addressed the patient as a person with contributions to make towards his own healthcare. Something to think about.  

Coming back to Mr. Samurai, after the initial treatment of Rituxan is over, and he has had a good response (yes, that is our hypothesis), I would release him to the care of his primary physician, with the request to keep me in the loop on monthly CBCs, and an appointment for 6 months later, unless there is an emergency of some sort. If at that time the disease is still aggressive, unless there are reasons why Fludarabine is contraindicated at that time (for reasons such as autoimmune diseases such as ITP, AIHA), I would initiate a series of standard RF therapy, hoping to get him into a long and deep remission. I prefer RF to RFC, because from what I have seen thus far, it seems to me that the inclusion of the alkylating agent Cyclophosphamide greatly adds to the toxicity of the regime, especially increased risk of neutropenia, without necessarily adding a great deal to increased efficacy. I could be wrong about this, and I will be the first to admit that a great deal more data is available on RFC, especially from the extensive work done at M. D. Anderson, than on RF. But there is growing number of oncologists and CLL experts who are coming around to the opinion that similar response rates can be obtained with RF, with less toxicity. If Mr. Samurai had a less worrisome prognosis, I might have been tempted to try RF "light" as a back-up to the initial salvo of Rituxan therapy, but I do not think that would be a variable option in his case, not if he flunked the first go around of Rituxan as frontline therapy for 8 weeks.

A bone marrow transplant, in the absence of perfectly matched sibling, is absolutely my last choice. Neither would I try Cladribine. This drug is another purine analogue, like Fludarabine, just that there is a lot less clinical information available about it, and I see no reason to try it instead of Fludarabine. I see no reason to subject Mr. Samurai to the additional risk of a less well understood drug, when it is likely to be no more effective than Fludarabine, perhaps less so. 

As for waiting a bit before initiating any therapy, while I agree that 90% bone marrow cellularity is clearly preferable to 100% cellularity, I do not see the advantage in letting the disease progress further, to the stage where the bone marrow is even more compromised, especially since the first line of defense I planned to use did not involve much risk of toxicity. My concern would be that at more advanced stage, there would be decreased number of effector cells such as T-cells, NK cells, macrophages, neutrophils, etc., to work with the Rituxan and even those present will be confused and ineffective ("anergised") because of the conflicting cytokines released by the CLL cells. There is also the risk that the patient may develop one of the many autoimmune problems that CLL patients are prone to, further complicating therapy decisions. Lastly, there is the risk that with increasing tumor load, a "clonal evolution" event may become more likely, simply based on the larger number of neoplastic cells that could mutate into something more aggressive.

Furthermore, I saw nothing to be gained by waiting, it is not likely that Mr. Samurai will get better on his own, or that Rituxan will become a cheaper drug in the near future. Nor did I see any reason to expect major breakthroughs in research findings that will give me an entirely new and more effective method of treating Mr. Samurai, in the limited time frame available to him. If his disease was at a much earlier stage, or if it was of a more smoldering type and one could see waiting for 1-2 years without compromising therapy choices or quality of life, there would be some point in waiting in the hope that some new information would become available in that period of time, information that would change the ballgame in a big way. 

Another debating point is whether Rituxan as frontline is sufficient, or if one should have gone directly to RF or RFC. As for the efficacy of Rituxan in clearing out the bone marrow, that is a good point to think about. This was the specific reason why I recommended inclusion of additional immunomodulatory drugs, namely GM-CSF, to further boost the efficacy of Rituxan, in the hope that this would be enough to tilt the balance in Mr. Samurai's favor. It also helps that there is no mention of bulky lymph nodes in Mr. Samurai's case. One school of thought holds that bulky lymph nodes pose a difficult challenge in trying to get a clean remission. In either case, an opening salvo of Rituxan complies with the cardinal rule of physicians, "this above all, do no harm". 

Abstract

CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. 

Durig J, Naschar M, Schmucker U, Renzing-Kohler K, Holter T, Huttmann A, Duhrsen U. 

Department of Haematology, Medical Faculty, University of Essen, Essen, Germany. 

Employing a multicolour flow cytometry assay, 133 B-chronic lymphocytic leukaemia (B-CLL) cases were analysed for surface expression of CD38. Based on a cut-off value of 20%, CLL patients were categorised into a CD38-positive (> or = 20%, n = 56) and a CD38- negative subgroup (< 20%, n = 77) and separately analysed for clinical and laboratory parameters. Patients in the CD38-positive cohort were characterised by an unfavourable clinical course with a more advanced disease stage, poor responsiveness to chemotherapy, short time to initiation of first treatment and shorter survival. In contrast, the CD38- negative group required minimal or no treatment, remained treatment-free for a longer time period and had prolonged survival (P < 0.05). CD38 expression was a robust marker in the majority of patients in that it was stable over time and not significantly influenced by chemotherapy. In conclusion, our data confirm recent studies suggesting a role of CD38 as a predictor of clinical outcome in patients with B-CLL.

PMID: 11840260 
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