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A Morality Tale of Two Friends

Date: May 21, 2024

CLL patients do not make good ostriches.

An 'Opinion Leader' who should know better had this to say about getting prognostic testing, especially for people who have been through therapy: what is the point in finding out the FISH cytogenetics or the IgVH gene mutation status, since the patient has already been through one or more rounds of therapy? What good does it do, except cause more worry?

That attitude does a lot of harm — in my opinion. Yes, knowledge can be intimidating and scary, especially if the news is not good news. But that does not mean ostrich-like behavior is safer. At a time when there is rapid change in our understanding of this disease and better options can be guided by risk stratification, there is absolutely no excuse for going into the next round of therapy 'blind'. I will be the first to acknowledge we do not have all the answers yet. But even partial answers are better than total (perhaps even willful?) ignorance!

I think there are very good reasons for finding out your FISH status prior to initiating therapy, even if you have been through prior therapy. And if you have never had the IgVH gene mutation status done, it is now possible to get it done without having to go to one of the expert centers. Please read our recent article on the deal we negotiated with Quest Diagnostics. There are still a few bugs to be worked out of the logistics, and you have to take responsibility for making sure your blood sample is sent to the correct address in California and that the correct codes are used for the 'package deals', but that is not hard to do if you are determined to become involved in your own healthcare. Quest also offers a 'monitoring' package that you can use to keep an eye out for 'clonal evolution'. For the record, neither PC nor I nor any of the Board Members of CLL Topics have any financial or other conflicts of interest with Quest, or any other company or organization. None. Zip. Nada. All of us work 100% pro-bono.

A Tale of Two Friends

'Harvey' (our strictly hypothetical hero and lovable Round Headed Kid) met John while waiting at his local oncologist's office. (Fictional characters have imaginary friends. 'John' is another hypothetical patient I just made up). Both were newly diagnosed CLL patients, roughly the same age group. But that is where the similarity ended. Harvey is an information geek, quintessential type A personality that demanded he get involved and get pro-active in learning as much as he could about this disease. John was a lot more laid back, willing to leave the heavy lifting to the guys wearing white coats. Frankly, he did not want to know all the details that Harvey kept digging up. Why create more worry and tension, he said. The doctor had things well in hand.

Harvey bugged his doctor and finally got his FISH test done, and very relieved to find he had the relatively benign 13q deletion only. John did not get around to it. When it was time for therapy, Harvey pushed for Rituxan as single agent therapy. John went with the 'gold standard' chemotherapy drug fludarabine as a single agent, in keeping with his philosophy of 'going with the flow'. Both friends got good responses. John had slightly deeper response than Harvey. True, he also developed a painful case of shingles, something that Harvey avoided. As the months went by, John's lymphocyte count stayed low. One year after therapy, Harvey's counts had crept up slowly to where next round of therapy became an issue. John felt a little smug, his fludarabine remission was still holding.

Re-tread Time

Given his nature, Harvey had researched and read all about 'clonal evolution'. Darwin's theory of evolution works even in cancer cell populations. CLL cells are genetically unstable by their very nature, and over time new cells with different mutations may crop up in their midst. If the new mutation gives the new baby clone a survival advantage over the older clone, it will gradually take over, become the dominant species. This process of gathering additional new mutations can happen all by itself, but the chances of it happening are much higher when exposed to mutagenic chemotherapy drugs. That was precisely why Harvey chose to go with Rituxan, because it did not carry the risk of additional mutagenicity. Fludarabine, on the other hand, had a pretty serious reputation for causing new mutations, secondary cancers, as well as transformation of the original CLL to more dangerous versions, such as Richter's transformation.

When it was time to go for second round of therapy, Harvey got his doctor to order FISH test again. Doc grumbled and it took Harvey some fancy negotiating skills to sell him. 13q deletion is as good as it gets, the doctor said, and proof of the pudding, Harvey responded nicely to Rituxan as single agent. What is the problem? All he has to do is repeat the Rituxan single agent therapy, get a good response, stop all this FISH monitoring nonsense. But Harvey insisted, and to get the patient off of his back doctor agreed to a repeat FISH test. The results came back in a week or so. Harvey was devastated to find that his CLL had evolved, there was a new clone with the more dangerous 11q (ATM) deletion, as well as the original 13q deletion.

After he got over his initial shock, Harvey did his usual thorough job of researching his situation. People with 11q (ATM gene) deletion tend to have more of their disease centered in lymph nodes, and sure enough Harvey noticed his lymph nodes were larger this time around. There was also concern that Rituxan (or Campath, the other monoclonal drug) does not work very well on large lymph nodes. To Harvey that meant two things: he had better not wait till the nodes got too big, lulled into a false sense of security by the low lymphocyte counts. His peripheral blood numbers were no more than the tip of the iceberg, the real tumor load lay in the lymph nodes. The second action item was to try and make the Rituxan work a little harder, with low toxicity adjuvants. The rest is (fictional) history, and you can read all about the 'Round Headed Kid' RHK protocol that Harvey designed for himself on this website.

As fate would have it, John too had a relatively benign 'normal karyotype' FISH cytogenetics to begin with, even though he did not know it. His frontline fludarabine therapy killed of most of these CLL cells, but left him a little ticking present at the end of therapy. A few CLL cells morphed, picked up a new deletion as a result of the trauma of fludarabine therapy, they now had a deletion in their 17p chromosome, deletion of the important tumor suppresser gene 17p53. Little by little, this new tougher-to-kill clone took over the neighborhood. A couple of years after Harvey had settled into his annual 'RHK' re-tread routine, John finally got around to scheduling his next round of therapy. Since fludarabine worked so well for him the last time around, he saw no reason to mess with a good thing.

If only he had pushed to get his FISH test done, at least before going in for the second round of therapy! His prognosis had changed dramatically, partly due to his first therapy choice. He was now 'Bucket C', the 17p53 chromosomal deletion meant there was slim to no chance he would respond to fludarabine therapy. Sure enough, he got almost no response to fludarabine the second time around. All that pain and suffering of going through heavy dose chemotherapy, and he had nothing to show for it. If I really wanted to push this morality story to the limits, this is where I would say John developed Richter's syndrome, which has a very short fuse indeed. Or perhaps I would inflict him with an aggressive form of skin cancer. Secondary cancers such as these can go ballistic during periods of deep immune suppression brought about by chemotherapy.

Would John have done better by being less of an ostrich? I think so. Even with his original Bucket A status with normal karyotype FISH, he might have pushed and negotiated for a less mutagenic therapy, which may, just may have avoided the clonal evolution altogether. (But no guarantee, there are none in this cancer business, just a matter of reducing risks. Remember, Harvey had clonal evolution to a worse prognostic bucket, even though he did his best to avoid mutagenic therapy)! Certainly, getting a FISH monitoring test after his first round would have highlighted the clonal evolution both to John and his doctor, made it obvious a second round of fludarabine was contra-indicated. He might have considered a Campath based therapy - this monoclonal antibody has been proven to work even in 17p53 deleted cases. Wrong choices based on lack of prognostic information can be very dangerous indeed.

The stark truth of it is that all too often much of the latest information on CLL therapy choices and modern prognostic testing has not percolated down to the level of the local healthcare provider. It is intimidating, it is frustrating, and unfair, but I am convinced your active participation and understanding is mandatory, if you are to play the hand you are dealt to best possible conclusion. Here are a few links to get you started.

Prognostic and Monitoring Test Packages;
Fludarabine Monotherapy No Longer Gold Standard;
The Difficult Case of the Round Headed Kid;
Good News for the Tough Cases;
Dawn of a New Era;
Are We There Yet?;
Shopping for Therapies;
Diagnosing Your Doctor;
Journey of a Newly Diagnosed Patient.

Be well, stay smart

Chaya
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