Combination Immunotherapy 

The Continuing Saga of the Round-Headed Kid

February 26, 2024

by Chaya Venkat

The RHK Protocol Boosts Harvey's Response

Several of you wrote and asked how Harvey was doing. So I thought I would update you on the continuing saga of Harvey, our round-headed hero, champion of all depressed and scared Bucket C CLL patients. Those of you who are not familiar with Harvey's case history, you can read the whole story by clicking here. I have also given links to the various articles that contributed to Harvey's logic in coming up with his game plan. You will not get much out of this article unless you are willing to follow the whole logic thread.

Let me repeat for the record that Harvey is a hypothetical patient, and any resemblances between him and any living person that you think you see is clearly due to your own over-active imagination. This is just one more hypothetical case history, a technique I use often to make a few points. Remember too that what may be right for Harvey may not be right for any other patient. You really have to work the issues out for yourself, do your homework and have serious discussions with your doctors, before deciding on the game plan that is right for you. All I am trying to do with this case history is to focus your attention on some rather interesting concepts. With those necessary and important caveats out of the way, let us get on with it.

Life Is All About Hitting Curve Balls Out of the Ballpark:

Here is a brief synopsis of what has transpired thus far. Harvey was diagnosed with CLL a few years back. His particular brand of CLL seemed to be pretty indolent. When the CBC started looking a little shabby, red blood counts and platelets heading lower while lymphocyte numbers and lymph nodes size grew larger, Harvey went for eight weeks of Rituxan-only as frontline therapy, at the standard 375 mg/m2. No problems with the mouse juice, he tolerated it very well. Things were cool, he got a nice remission that lasted just about one year, which is pretty long by CLL standards. All in all, he was pretty content. His game plan was to repeat the Rituxan only, as needed.

Then everything went to hell in a hand basket. A routine FISH monitoring test identified a new and more dangerous clone. In addition to his original rather benign 13q deletion, a fraction of Harvey's CLL clonal cells had acquired the dreaded 11q deletion as well. Repeating the FISH a couple of months later confirmed his worst fears, the fraction of CLL cells that had both the 13q and 11q deletions was overtaking the just 13q deleted variety, at a rapid clip. As we reported in the earlier article, Harvey did some heavy duty reading to get a better fix on things. The upshot of many long nights in front of his laptop was a protocol he defined for himself, that might give him a good chance at a low toxicity route to controlling the CLL. For lack of a better name for it, we will call it the "Round-headed Kid" protocol, "RHK" for short.

The RHK Protocol:

Clearly, things had changed since the last time around when he got by on plain vanilla Rituxan therapy. No getting away from that, the new 11q deletion has changed his status from Bucket A to Bucket C. 11q deletion meant deletion of the ATM gatekeeper gene, and very often this also meant that the critical tumor suppressor TP53 gene function was also compromised. ATM gene is the one that wakes up the TP53 gene. With ATM gene gone AWOL, one of the major mechanisms for proper function of TP53 was also likely to be compromised, to some degree. ("Cytogenetics of ATM and TP53") Since defects in ATM and/or TP53 function do not seem to work well with purine analogs and alkylating agents, Harvey decided not to go that route. He was not sure if the same logic applied to combo therapies that used stuff like fludarabine, pentostatin (both purine analogs) and cyclophosphamide (alkylating agent), as in the popular RPC and FRC combo therapies, but he decided not to look in that direction for solutions, not just yet. Some day he could have few other choices but go that route, but that day had not arrived yet.

The two monoclonal antibodies, Rituxan and Campath, were going to be important in his life. Since he had responded so well to Rituxan therapy the last time around (no adverse reactions worth writing home about and a nice long remission for a full year), he decided he would try his luck again and keep Campath as a backup.

Would Rituxan be enough? After much reading he came to the conclusion that the problem was not the 11q deletion per se since both Campath and Rituxan did not seem to care about that. They both seemed to have cell-kill mechanisms that got around the defective ATM and TP53 pathways. The problem was that monoclonals did not work all that well with bulky lymph nodes (see "Campath: Looking Better and Better"), and this time around he certainly had larger lymph nodes going in to therapy, and many more of them as well. There were the bunch all around his jaw line that gave him the willies when he looked in the mirror as he shaved every morning. Then there were the inguinal nodes that only his girl friend knew about, and the solitary lymph node in his armpit that his new oncologist swore was the largest one of them all, but Harvey could never even locate the darned thing! Doctors must grow finely calibrated fingertips in medical school, he thought. Harvey smiled to himself as he remembered his first oncologist, the one who told him his spleen was enlarged (a catscan proved later that he was wrong). But get this, the oncologist also told him it was 15.2 cms in size, just by poking around with his fingers. That's right, 15.2 centimeters exactly, not 15.1 centimeters and not 15.3 centimeters either. As an engineer, Harvey liked precision more than most people, but he felt there was no way the oncologist could have been that precise, not just by using his fingers! Harvey simply found a new oncologist.

How to Make a Good Thing Better:

How does one go about goosing up Rituxan therapy, to make it work better with bulky lymph nodes? One night, after long hours of reading until he was both exhausted and yet too jittery and wired to be able to sleep, he watched a little late night TV to help him relax, some stuff about hunting down Al Qaeda. Harvey fell asleep on the couch and dreamed he was in Afghanistan. Things were a little mixed up as they often are in dreams. He was trying to help the Special Ops track down some well known terrorists, all of whom had "CD20" tattooed on their foreheads for some strange reason. The problem was that the terrorists were holed up in villages with a whole lot of innocent civilians, women and children. In his dream, some of the houses looked long and lumpy, sort of like the lymph nodes he had under his jaw, and some of the houses had a strange bleached-bone look to them. The villagers were being forced to protect the terrorists with their own bodies (acting very much like "nurse-like cells") and there was no way the Special Ops or Marines could get to the bad guys without literally busting up all the bone marrow and lymph node houses, killing terrorists and innocent civilians alike.

Harvey was the hero of his own dream. He came up with the perfect solution. How about throwing in some smoke grenades into the village, but first making sure the whole village was surrounded so that no one could get past the cordon of Marines? The heavy smoke would make it impossible for anyone to stay tucked away indoors in the bone/lymph node houses, forcing them to come streaming out into the open, just to breathe. Sure enough, that is exactly what happened in Harvey's dream. Kids, women, old folks, and the bad guys with CD20 etched out on their foreheads, every one came running out. It was pretty easy to nab the bad guys at that point, their CD20 markers gave them away. Sure, the villagers grumbled, kids cried at being woken up and forced to come out into the cold air in the middle of the night. But no real harm was done and soon enough things quieted down and the innocent villagers wandered back home. The Marines repeated the same process several times more, once every week or so, just to make sure there were no terrorists who managed to stay indoors even with all that smoke the first time around. The hope was that none of the terrorists managed to slip past the Marine cordon around the village.

After that, the directive went out from HQ, everything must be done to avoid a similar situation. The few remaining terrorists must not be allowed to slip by and find safe havens elsewhere, fertile ground with built-in resources where they could hide from just punishment. The Special Ops guys had won the battle with Harvey's help, but it was even more important not to lose the whole war by getting lazy afterwards. Harvey woke up at that point and stumbled off to bed, after switching off the TV (it was an old John Wayne movie and the sound of the shootout was too loud even for Harvey to sleep through).

They Should Teach Listening Skills in Medical School:

Harvey had an appointment to see his hematologist the next day. Lucky for Harvey, he lived close to one of the best cancer centers in the country, and even more lucky that his particular guy was that rare combination, a well-informed and smart specialist that had somehow not forgotten the art of listening.

While Harvey's peripheral blood absolute lymphocyte count was not particularly high and the rest of his blood counts were in the normal range, Doc too was worried with the rate at which the lymph nodes were growing. There were too many of them getting too large and too quickly. Doc agreed with Harvey that it was probably time for therapy. The million dollar question was, of course, what therapy? Doc laid out Harvey's options, including popular combo therapies FRC and RPC. (R: Rituxan; F: fludarabine; C: cyclophosphamide; P: pentostatin). After doing the right thing and pointing out the advantages of going with relatively well understood combos like this, Doc sat back and heard Harvey out. Harvey wanted to try out his "RHK protocol", combining the specific targeting capability of Rituxan with Neupogen's ability to get the cancer cells get kicked out of their safe havens of lymph nodes and bone marrow. While there was still a lot of controversy on exactly how cancer cell-kill happened with Rituxan, there seemed to be consensus that a large part of the actual cell-kill was carried out by the patient's own immune system working to get rid of the CD20 positive cells tagged by Rituxan. If the RHK protocol was going to work, Harvey felt it had the best chance of doing so while he still had an active and effective immune system capable of working with Rituxan.

Oh yes, one more thing. Harvey's girl friend was a great believer of the virtues of green tea extracts, especially the polyphenol EGCG that green tea contained in large quantities. Heck, she had just named her new tricolor Aussie puppy "EGCG"! Harvey wanted to see if he could boost the performance of Rituxan and his own immune system by further tagging CLL cells with EGCG. After all, CLL cells have been shown to express lots of VEGF receptors, and EGCG tagged these receptors, effectively blocking them. He had this silly vision dozens of copies of his girl friend's new puppy hanging on to each CLL cell. "EGCG" was a cute and friendly puppy. But Harvey could see how dozens of molecules of EGCG hanging on to each CLL cell would make the cancer cell a lot more vulnerable to attack.

Fortunately for Harvey, Doc had also done a lot of reading on EGCG, the most abundant polyphenol found in green tea. Lots of good science coming together seemed to indicate that EGCG may help control the VEGF and angiogenesis aspects of CLL ("Do You Like Drinking Green Tea?"). Doc agreed when Harvey suggested that he would like to continue taking his high potency green tea extract capsules twice a day, as well as using the green tea extract skin cream his girl friend had made for him ("The How Is Often as Important as the What in Chemotherapy"). Frankly, Harvey was not sure how much of the EGCG in the capsules actually got to his lymph nodes, how much of it was destroyed and eliminated in his gut and liver. The transdermal cream made a lot more sense to him, and it was no big deal to use it as a body lotion, just prior to doing his daily workout on the treadmill. Harvey also got permission to continue his Singulair ("Chronic Inflammation and What You Can Do About It") and cimetidine ("Recruiting NK cells") all through the therapy period. Harvey went home to give the good news to his girl friend, that Doc gave Harvey sound advice about more standard therapies, but in the final analysis he was willing to listen to a patient who had clearly taken the trouble to do his home work, did not have unrealistic expectations, and was willing to take responsibility for his own decisions.

Gentle reader, I cannot refrain from a little sermon here. Communication is a two way street; even the most caring and open-minded of doctors have no choice but play it by the book when confronted by patients looking for miracles, with the attitude that says "Don't bother me with the details, just cure me, give me a pill or potion. Do it quick, do it with no pain or fuss, do it NOW!! I have cancer and I am entitled to act like a real brat, and if the result are less than stellar, I can always sue you for malpractice" An informed consumer willing to work with his healthcare providers and advisors gets better information, choices and a more custom-fit deal. The same is true of most other aspects of life. If you do not take the trouble to learn, understand, and think through stuff, do the heavy lifting yourself, there is a reasonably high chance that you will get the standard response from your doctors. Mind you, that may indeed be the best choice for you, but you might always wonder about the path less traveled, what you might have missed because of not getting involved and working the issues yourself. This is your life we are talking about. What gets higher priority than that? How can you be too busy with your job or whatever, too busy to pay attention to the decisions regarding your own therapy? And if you cannot be bothered to give it priority, how can you expect the rest of the world to care more about it than you care yourself?

So, How Did Harvey Do on this RHK Protocol?

To put it mildly, Harvey had a great response to the RHK protocol, better than he or Doc had expected. His peripheral blood WBC was not all that high to begin with, but nevertheless it was gratifying to see every single last item on his CBC get into the normal ranges just two days after the very first infusion of Rituxan. But the real test was, of course, how his lymph nodes reacted. Unlike the first time Harvey had tried Rituxan about a year ago, this time there was definite shrinking of the lymph nodes right from the word go. As we speak, Harvey is just about to finish the last of the 4 weeks of RHK protocol, consisting of Rituxan + Neupogen + EGCG. The lymph nodes are less than a third of the size they used to be which by itself was a much better response than he got the year before. No bone marrow testing has been done yet, but the very healthy numbers on his CBC with regard to red blood cells, platelets, etc. was a good indicator that his marrow was doing just fine, thank you.

Harvey now faced a dilemma. What should he do next? As he saw it, there were three options:

• Do Nothing Further. He could take his better-than-expected response as is, and hope that the lymph nodes continue shrinking further (Rituxan does stay around in the blood for quite a few weeks after the last infusion, it continued working on Harvey's lymph nodes for a full 2 months the last time around). Since he got a full year remission the last time around, there was good reason to hope that with the deeper response this time around he may do better this time on the length of remission as well. The remission may also last longer if he took care to "maintain" it with his chemoprevention efforts ("Life after Rituxan: How to Keep the Party Going"). Who knows what new drugs and options will be available to Harvey in a year or two? Meanwhile, he has burnt very few bridges and has done very little to damage his immune system.

• Go with the Momentum. Since Rituxan plus Neupogen plus EGCG was working so well for him, and he had so few side effects to complain about, should he continue the winning streak, add another four weeks of the same thing, bringing up the whole total to 8 weeks of therapy? There was a great deal of allure to this approach, he had a pretty good idea of the downside in terms of side-effects and he was not adding any new drugs and therefore not adding any unforeseen toxicities to the RHK regimen. What if the additional four weeks of therapy made all the difference in getting his lymph nodes cleaned out completely? Dare he hope to get a full and deep CR (complete response) or even a PCR negative molecular remission ("PCR Negative Remission: Is this a Cure?") with just Rituxan? (Well. Not just Rituxan, credit must also be given to the smoke grenade of Neupogen flushing out CLL cells, and dozens of cute but exhausting EGCG puppies making life impossible for the darn CLL cells).

• Raise the Stakes. The last option Harvey is considering is adding subcutaneous Campath at the back-end of his 4 weeks of the RHK protocol, as a way of trying to get a full-blown PCR negative (molecular) response. ("Campath, Looking Better and Better"). Several articles reported that patients upgraded the quality of their response to original therapy by adding sub-q Campath at the backend, as a way of mopping up the few remaining CLL cells. In fact, Harvey remembered seeing clinical trials announced by the Eastern Cooperative Oncology Group (ECOG), where patients had the combo RPC therapy, followed by sub-q Campath for clean up of MRD (Minimum Residual Disease). Harvey liked his combination better, Rituxan plus Neupogen plus EGCG was a lot easier to handle than the heavy duty chemo part of RPC. Given his 11q deletion status, he was just as happy not to try fludarabine, pentostatin or cyclophosphamide.

Last I heard, Harvey was still mulling over these three options. When he decides and implements one of the options, and gets some additional results, I will let you know. In the meantime, Harvey said I could publish this chart (above) which shows his absolute lymphocyte count over the past year or so. It shows his first response to Rituxan-only therapy about a year ago, as well as his present response to the RHK protocol. You can see the very sharp response right from the word go, this time around. And yes, Harvey adds that the rest of all his counts, too,  are doing much better this time around. Keep your fingers crossed for our hero, may all his lymph nodes continue shrinking all the way!

This is the story of a hypothetical patient. Some of you wanted to know why I called my hero Harvey, and why his chosen therapy is called the RHK protocol. The answer to the first question is that I liked the movie starring James Stewart and his imaginary six foot tall rabbit named Harvey. The answer to the second question is that I like the Peanuts cartoons - always had a soft corner for Charlie Brown. The Round-headed Kid is very lovable in his innocence and optimism and is always trying to do his best even in the worst of circumstances. That is what courage is all about, doing one's best under trying circumstance. That is what makes Harvey, the Round-headed Kid, my personal hero.

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