Case Studies

ZAP-70: Why Should You Care?

Date: April 4, 2003

by Chaya Venkat

Case Histories of Jane and John

Related Article:
ZAP-70 and IgVH Gene Mutation: Worth Understanding

The last two articles on ZAP-70 were based on actual technical papers by the real experts. This article is purely teaching oriented, based on case scenarios I created for two totally fictitious patients to illustrate why I think this and other, better, yet-to-be-discovered prognostic indicators can make the difference between life and death, health and sickness for CLL patients.
__________

Case history of Jane

Jane is a healthy, fit and vigorous young woman, married, with two pre-teen kids. She goes in for her annual check-up. Doc says WBC is slightly elevated, and your lymph nodes in the neck are a little inflamed; probably you have a bug of some sort, why don't you come back in a couple of weeks and we will see if it is still high. Couple of weeks later, WBC is still at 10K, but everything else looks good. Jane is lucky to have a caring and detail oriented GP, he orders a basic flow cytometry just to be sure. You guessed it, Jane has Rai stage-1 CLL. Doc sends her to highly regards local oncologist for follow-up.
_________

Scenario 1 for Jane:

Local oncologist confirms the CLL diagnosis, confirmed by CD5/CD19/CD23 positive clonal population, light chain lambda restricted. Everything looks quiet, and Jane has a Beta-2-microglobulin of 1.8, below the cut-off point of 2.0 for good prognosis. Oncologist tells Jane to go home, take care of herself and her family, she is likely to be in watch and wait for a long time. She should have her CBC done every three months, just to keep an eye on things. 

Nothing much happens for six months. Then all hell breaks loose. Jane's WBC starts heading up rapidly, along with B2M levels. Over a period of less than 2 months, the WBC goes from 12K where it had been for a while to almost 45K. B2M goes from 1.8 to 3.1. New lymph nodes pop up all along her jaw. Bad news, oncologist tells Jane. Looks like you have an aggressive form of CLL after all, with this very short lymphocyte doubling time. 

Local guy prides himself on being up-to-date, he has heard of this new monoclonal antibody called Rituxan, works very well in some CLL patients, and it has a good toxicity profile. Unfortunately, Jane has only low expression of CD20 marker (40%, dim 1+ intensity), oncologist thinks maybe Rituxan-only therapy will not be good enough for this aggressive disease. For this relatively young patient (45 years old), bone marrow transplant may be an option for a possible cure. But Jane has no siblings with good bone marrow match, and the decision is made to go with Fludarabine therapy for now, may be MUD (Matched Unrelated Donor) bone marrow transplant or one of those mini-allogeneic stem cell transplants can be considered later on. Fludarabine is still the gold standard for CLL, he tells Jane. Oncologist decides that Jane should go for six rounds of Fludarabine, full strength. 

Fludarabine therapy certainly brings down her WBC, and lymph nodes. But in Jane's case the therapy also leaves her deeply neutropenic, and vulnerable to infections of all sorts. Neupogen shots don't seem to help much, and the reduced red blood cells and hemoglobin levels leave her tired all the time. Jane quits her job, her kids learn to fend for themselves a lot more. Last we heard, less than 2 years after her CLL diagnosis and four months after finishing the Fludarabine therapy, Jane is in the hospital for the second time with a bad case of pneumonia, after having spent the whole summer dealing with very painful shingles. She worries she may now be refractory to Fludarabine, burning bridges and shutting out other therapy options down the line; she is scared about going the bone marrow transplant route. 
__________

Scenario 2 for Jane:

Local guy prides himself on being up-to-date, he has heard of this new prognostic indicator called ZAP-70, but very few labs are equipped to do the test. Oncologist calls in a few favors, and gets one of the big CLL consortium centers to run the test for Jane. Good news, Jane has only 8% ZAP-70 positive cells, well below the  20% cut-off point, indicating she is almost sure to have the IgVH gene mutated form of CLL and a terrific prognosis for long and healthy life. Oncologist tells her to relax, she may never need therapy, or at least not for a long time. Jane should just go home, take care of herself and her family, she is likely to be in watch and wait for  a long time. She should have her CBC done every three months, just to keep an eye on things. 

Nothing much happens for six months. Then all hell breaks loose. Jane's WBC starts heading up rapidly, along with B2M levels. Over a period of less than 2 months, the WBC goes from 12K where it had been for a while to almost 45K. B2M goes from 1.8 to 3.1. New lymph nodes pop up all along her jaw. Oncologist is worried at the short lymphocyte doubling time, and the elevated B2M. He goes back and reads again the papers on ZAP-70 that his friend the CLL expert had sent him, the data seems compelling, Jane is one of the lucky ones with good prognosis. She is not supposed to have an aggressive form of CLL! What gives?

After scratching his head for a while, he calls Jane in for a consultation. He asks her if she had any recent infections. Jane says no at first, then remembers that bad "cold sore" she had in her mouth for several weeks after she had dental cleaning a few months back. It is still there, not quite healed. Does that count? You bet, says the oncologist, it counts if the sore was caused by Herpes simplex. Sure enough, test comes back positive for Herpes Simplex. Oncologist puts her on a month long course of Famvir, tells her to have weekly CBCs done for a while till the whole mess clears up.

Two months later, Jane's WBC has begun to come down as fast as it had gone up the past few months. Nodes receded to the levels they were back when Jane was first diagnosed, and that pesky B2M is back down to 1.8. Oncologist nods with satisfaction. False alarm, he tells Jane. You are fine, the CLL is not acting up, it was just a viral infection that drove up your WBC. We have the virus controlled now, and everything is back down to normal. He warns Jane to make sure she takes a broad spectrum anti-biotic and anti-viral, next time she goes in for heavy duty dental work. Last we heard, it is 8 years later and Jane's youngest kid was heading to college; but for the quarterly CBC she gets done to keep her oncologist happy, she does not spend much time thinking about her CLL. 
___________

Comment:

Sure, I gilded the lily a little, but it is clear which is a better scenario for our heroine. But for the strong prognostic indication of the ZAP-70 test suggesting caution before initiating therapy, local oncologist would have gone with the evidence he had, short lymphocyte doubling time, increased B2M levels, and advancing lymphadenopathy (fancy words for swelling lymph nodes), and not gone the extra mile to look for other possible reasons for the elevated WBC. If you want to read more about viral drivers of our disease, visit Viral Drivers on this website. In P.C.'s case, we believe that the rapid ramp up in lymphocyte counts was as a result of viral infections and there was an equally rapid ramp down after anti-viral treatment .

_________

Case history of John

Meet our second fictitious patient, John. One year into his early retirement to enjoy the good life, John begins to feel a little under the weather, not enjoying his daily golf game as much as he thought he would. His wife bugs him into going in for a medical check-up, it has been ages since he saw a doctor! To cut to the chase, after a couple of go-rounds with the GP, John is sent to see the only oncologist in town. Blood tests come back, John has early stage CLL. The CBC shows he has 20K white blood count, and slightly reduced hemoglobin levels, perhaps accounting for his tiredness after the 8th hole.
________

Scenario - 1 for John:

Local oncologist looks up CLL in his desk reference, he is an all-purpose cancer guy, not an expert on hematology. After doing his homework, he tells John CLL is an indolent form of cancer, there is no known cure for it. The best thing to do is watch and wait, and when symptoms start showing up, he can take care of it with Chlorambucil or the new fangled Fludarabine that seems to be the thing these days. He also tells John he can go to the Consortium doctors in Houston if he feels he wants a second opinion, but at 20K WBC in his peripheral blood he is at early stage, it will probably be a while before anything needs to be done. He should get a standard CBC blood test, every 3 months, to keep on eye on things. This sounds great to John. He hates going to doctors and hospitals anyway. 

One year later, John wakes up in the middle of the night with intense and shooting pain in his abdomen, and starts throwing up. His wife takes him to the emergency room, where they do a CAT scan to make sure it is not a rupturing appendix. No, appendix is fine, but John has massive and large lymph nodes deep in his abdomen, pressing on other vital organs and blood vessels. Local oncologist is surprised. After all, the CBC blood tests did not show any rapid increase in WBC, still only at 40K, there was no reason to have worried or done extra tests. Now he is worried, and insists that John make the trip to the big cancer center a few hundred miles away. 

The experts do all sorts of test, including bone marrow biopsy, FISH analysis, flow-cytometry and ZAP-70 test. John's bone marrow is 100% hypercellular, and heavily compromised with diffuse lymphocyte infiltration. No wonder his red blood cells and hemoglobin had been heading south gradually over the past year, there was almost no room left in the bone marrow to produce any of the vital cell lines. He has deletion of p53 gene, suggesting an aggressive disease that is going to be hard to treat. ZAP-70 results confirm the bad news, at 45% positive ZAP-70, John is almost certain to have the unmutated IgVH gene, a very strong indicator of poor prognosis. Too bad that in John's case the aggressive nature of his disease was hidden, the lymphocyte count in his peripheral blood did not give an accurate picture of what was happening in his bone marrow, or the lymph nodes deep in his abdomen where they could not be seen or felt until almost too late. Too bad that he waited so long, he should have been in therapy right away, before the bone marrow got so heavily packed up with CLL, before his internal lymph nodes became so enlarged, before his general overall health became compromised. 

The experts recommend that John has few options but go for the big guns in combo chemotherapy. RFC therapy is getting some excellent results, with very good response rates. But with the dangerous p53 gene mutation, and the advanced stage of John's disease, there were no guarantees. Over the six months of the RFC  therapy, shuttling back and forth between home, local hospital for various infections, and the RFC therapy in the big cancer center, John had no chance to play any golf, and certainly not enough energy or desire to have enjoyed it, even if he had the time.  

To make a long and painful story short, John gets only a partial response from the RFC. There is still a lot of CLL left in his bone marrow. Doctors worry that with his aggressive sub-type of CLL, it will grow back only too quickly to the prior levels, making for a short remission. They suggest that he go in for Campath therapy, which has been shown to be successful in cleaning out bone marrow centered CLL. Bone marrow transplants was not an option that John wanted to consider. 

The Campath therapy was very rough, but seemed to work. Bone marrow biopsy two months after the last round of Campath said John's bone marrow was now clean. Doctors warned him his immune system is deeply suppressed with all the therapy, he is going to have to be very careful to avoid infections. Famous last words, in spite of taking all due precautions, John is back in the hospital a month later, with a severe case of unidentified, probably fungal infection. He died a week later, due to pneumonia and other systemic complications. 
_________

Scenario 2 for John:

Local oncologist looks up CLL in his desk reference, he is an all-purpose cancer guy, not an expert on hematology. After doing his homework, he tells John CLL is an indolent form of cancer, there is no cure for it. T The best thing to do is watch and wait, and when symptoms start showing up, he can take care of it with Chlorambucil or the new fangled Fludarabine that seems to be the thing these days. He also tells John he can go to the Consortium doctors in Houston if he feels he wants a second opinion, but at 20K WBC in his peripheral blood he is at early stage, it will probably be a while before anything needs to be done. All that needs to be done right now is the blood test every 3 months, to keep on eye on things. But just to be on the safe side, just to keep the wife happy, John agrees to go in for a second opinion and some additional tests at the big CLL consortium center a few hundred miles away. 

The experts do all sorts of test, including bone marrow biopsy, FISH analysis, flow-cytometry and ZAP-70 test. John's bone marrow is 50% hyper cellular, for a person of his age (60 years), it should only be 40% cellular. The lymphocyte infiltration was still nodular, which is good news, but beginning to show signs of becoming diffuse, which is not so good. FISH analysis showed he has deletion of p53 gene, suggesting an aggressive disease that is going to be hard to treat if allowed to get out of hand. ZAP-70 results confirm the bad news, at 45% positive ZAP-70, John is almost certain to have the unmutated IgVH gene, a very strong indicator of poor prognosis. 

It is very lucky that in John's case the aggressive nature of his disease was discovered early, before his bone marrow got too infiltrated and lymph nodes got to be too large to respond well. The ZAP-70 result was the thing that clinched the argument: he needed therapy, he needed it now, and it had better be strong enough to get him a good response. The experts recommend RFC therapy, which has been getting some excellent results, especially when it is used in relatively early stage patients like John, who are in otherwise good general health. 

To make a long story short, John grumbles his way through the six months it took for the RFC therapy, precious little time left for golf, what with all the driving back and forth between home and the cancer center for RFC therapy. But it was worth it, last weekend he went out to the golf course to celebrate his PCR negative response to the RFC therapy, with the new set of clubs his wife got him for Christmas. 
___________

Comment:

OK, OK, I overdid the scenarios, just a little. But you get my drift. It is as dangerous to over-treat a patient like Jane, with an indolent disease that did not require the therapy. It is equally dangerous to wait too long before treating an aggressive disease like John's, with poor prognosis if it is allowed to get out of control. The therapy decisions you and your oncologists make are going to be only as good as the information available to you. There is a lot happening on the CLL front, new things we are finding out all the time. Time you spend learning more about it will make your decisions that much smarter. 

John and Jane are fictitious patients. Like them, we too do not have any control over the type of CLL we have. But, like them, we too have choices in the roads we decide to follow. Some will lead to long and healthy lives, some are so wrong they can possibly cost us our lives. Right now, the best we can do is play the hand we are dealt to best advantage. Going in blind is not the way to do that! Read and learn all you can about your prognosis, your therapy choices. Then engage your oncologist in helpful and constructive dialogue. Both he and you have strong reasons for wanting to have the best possible prognostic indicators to guide your decisions. 

And do one more thing: be an involved part of this community of patients, we are all stronger for helping each other. If you know of another CLL patient who is struggling with early stage therapy decisions, bring to their attention the recent news on prognostic indicators. Lobby with your local oncologists and consortium experts to get this new ZAP-70 test developed quickly, and implemented as standard test in the workup of newly diagnosed patients. Think of the lives you will save by becoming involved.