I posted about the possible use of adaptive therapy to treat CLL awhile back, and I have a question.
First, let me just mention what Adaptive Therapy is for anyone who hasn't heard of it: It's an approach to cancer that says, we can't eliminate this disease, and the longer you treat, the greater the possibility of resistance, and the greater the possibility of serious adverse events, so instead of trying to achieve uMRD, just treat it enough to keep CLL in check.
So for example, for a patient with an early diagnosis, where ALC is currently 10E9 with doubling time over a little over a year, treat the CLL with short term low dose drugs to bring the ALC to 5E9 instead of trying to reduce it by 3 or 4 orders of magnitude.
In this way, the microenvironment is largely left undisturbed, competition between clonal populations is maintained, competition between non-lymphocytic cells and CLL is maintained, and competition for metabolic resources is maintained.
Hopefully, by not to disturbing the bodies natural immune system, the slow burn of doubling in a little over a year can be maintained.
Then, for example, if you can bring the ALC population to 5E9, you've essentially bought yourself a year. Then, you can repeat the therapy, and thereby maintain CLL as a chronic condition indefinitely. And at these levels, prevent the crowding out by the lymphocytic cells that start to reduce the other RBC, platlets, and neutrophils.
Sorry for the long intro, but my question is, can anyone provide data or recommend what drug or drug combinations they've used or think could be used to bring about a modest reduction of ALC from 10E9 to 5E9.
I've looked at some results using ibrutinib and venetoclax, and venetoclax seems to very quickly reduce lymphocytic populations, even enough so it is dangerous, TLS, tumor lysis syndrome.
So just as an example, I was thinking 20mg of venetoclax, the lowest starting dose, for 2 weeks. And if you come close to the reduction, just stop, and then not treat again to ALC again hit 10E9, hopefully a year later.
I was also thinking possibly of adding 140mg of ibrutinib for those weeks too, because the 2nd drug would help prevent resistance if a clonal population had or developed a resistance to venetoclax. Using 2 drugs makes the possiblity less likely. What are the chances of a mutation forming that is resistance to both?
Thanks for reading, and thanks for your thoughts.
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Interesting treatment approach. Not familiar with adaptive theory being applied to CLL, but the people at Moffitt in Tampa, FL, have done some small patient studies with solid tumor cancers using the cyclical on/off treatment approach you describe. I have discussed a similar approach with my MO as a future strategy for my metastatic prostate cancer.
Here is a link to Moffitt's adaptive group and a press release on the small trial they did with PCa patients. You might consider contacting them, as several PCa patients have done so and are sharing their n=1 experiences and getting feedback from Moffitt. (Robert Gatenby and Alexander Anderson are the two people whose research I am most familiar with.)
Cancer Biology and Evolution, Moffitt Cancer Center
Thanks Cujoe, you nailed it. It was exactly there that I first read about this approach. This article from SciAm really describes the approach in detail. I contacted Dr Gatenby, and although, like you said, he works in solid mass tumors, he said, "because the lymphocytes divide in the bone marrow where they are subject to the same microenvironment constraints and signaling as solid mass tumors, the same approach is reasonable (paraphrasing here)."
PT - Good to know that you are in touch with some of the advanced researchers in this emergent field. With most treatments in solid tumors we know they eventually fail due to the emergence of resistant mutations. Many of the first-gen researchers came to medicine with mathematical backgrounds and applied concepts from evolution and gaming theories to cancer. The goal is not to ever allow the "survival of the fittest" to happen within a cancer population. Currently we seem to be throwing multiple drugs at cancer, seeking a more powerful effect. Gatenby talks about the possibility of an "extinction event" under certain circumstances, but the window for that is often a very narrow one in the disease progression.
I'm connected with a number of patients who are doing their own treatment programs that cycle testosterone from supraphysical level to castrate levels. The concept is similar to the 50% reduction-to-2 x cycle that Moffitt has used. The Hi-Lo T-cycling for PCa has been trialed at Johns Hopkins and is called BAT (Bipolar Androgen Therapy). As with most new advanced treatments, it has initially only been used with patients who have already been heavily treated. As a result, it is only currently available via clinical trials (and maybe under the supervision of Denmeade at Hopkins) and quite few patients are doing their own n=1 trials and sharing their results at Facebook sites and forums here on HU and elsewhere. The science is moving much faster that the clinic. AI is going to accelerate it even more.
Keep us posted if you decide to give adaptive theory a try. Through a set of pure luck circumstances at my PCa cancer center, I broke from the standard SOC protocol that would have likely driven me to resistant disease many years back. Looking back at my experience to date, I continue to wonder how many cancer patients who are "good responders" to up-front treatment might also be good candidates for testing the durability of those responses via treatment breaks aka "vacations". In my case, my QOL has been excellent, esp. vs what it would be under continuous treatment that blocks T.
I have not heard of Adaptive Therapy before, but I like the logic of this approach. I am decidedly not a doctor, so I can offer no definitive knowledge or evidence beyond supposition. I do think the issue you will most likely come up against, to my knowledge it's an untried and untested medication regime and as such the potential consequences and long term outcome is unknown. In my experience, doctors will not consider treatment outside accepted guidelines & clinical practice.
I say this because despite being treatment naive, I have the SLL tissue based version. There was some research that seemed to support the notion that clonal mutations in the lymph nodes could be key in explaining why some achieved uMRD and others became treatment resistant, had a shorter time to progression and/or transformation to a more aggressive disease. I also read that 2 different clonal populations can co-exist from the beginning, but the dominant clone not only keeps the other in check, it can mask its existence.
It appears that my CLL is indolent, my immune system is not stable and hasn't been for as long as I can remember. I am not obviously immunocompromised in terms of infection, contrary to expected disease progression, vaccinate me & my lymph nodes enlarge as expected, except they don't shrink back, just get bigger.
Autoimmunity has also been ruled out, despite worsening allergies and other signs that were suggestive of autoimmunity. My immune system has a hair trigger and the damage it's doing to my body is out of proportion to anything my bloods show. I have always questioned if this is due to the dysregulation of the my adaptive immune and complement system. Weirdly there is invariably a vascular/blood component triggered.
This is a long way of saying that, I asked my hematologist to complete genetic testing and bone marrow biopsy, if there were no adverse markers to consider a very limited course of FCR to reset my immune system, before it became completely compromised. The hope was it could be sufficient to provide a "functional" cure to the CLL/SLL. The risk/benefit analysis seemed worth it to me. the answer was a definitive NO and likely still believes I'm delusional. I think I have a signalling problem.
I'd be interested to know if you have discussed this with your doctors already?
ps: I can't see the locked symbol. You may want to lock your post. Apologies if I can't see for looking.
And yes, the doctors I have spoken to are pretty much as you described, reluctant to deviate from accepted practice on the grounds that repeated treated would create resistance.
I have to respect these doctors who have given their lives to the field and have tremendous real world experience, but with all due respect to them, I just don't see it.
1) if you treat with the same drug for a year or longer, that seems to be the condition that would provide a selective pressure long enough for resistance to develop
2) a short term treatment of 2 weeks, repeated annually, or even every 6 months, seems unlikely to be long enough to create resistance
3) if you due a two drug approach over those 2 weeks, the chance of a resistance mutation emerging that was resistant to both drugs seems highly unlikely
Despite the negative feedback so far, I still think this treatment for CLL has tremendous potential. And Dr Gatenby is having excellent success with it, so it's not "some crazy idea."
That is something that I would definitely like to see widespread by the time I need treatment. Not only cost-effective but easy on the patient too. I could pay a 2-week therapy once a year out of pocket. So bugger the insurance companies, no approval needed.
Well, first we need to get someone in the oncology community to do it, and then we need it to show it works. You just don’t know. I’m obviously an advocate of trying, but without real life data, who knows if it is a better approach than trying to obtain uMRD. Although Wishing1202 posted that he’s heard of it being used successfully in CLL. I hope he can provide more details.
Do you have CLL? If so, please update your bio do that we can better address your question about Adaptive Therapy.
The Amplify Trial is testing the short term use of Venetoclax and BTKi. FDA could approve in 2025. If they do, then many of us will have a treatment that we can use multiple times.
Venetoclax + Ob is a phenomenal first line treatment that will give 3,5,7 year remissions for most people. My ALC went from 120 to 4 after day 1 of treatment. Would I have preferred to take Venetoclax every few months indefinitely to keep my ALC at 60 rather than achieve UMRD by taking V+O for a year? No way.
"My ALC went from 120 to 4 after day 1 of treatment."
That is incredible, and I have seen this reported in many trials. Venetoclax, especially, is so effective its mind boggling right out of the gates. But it becomes a lot harder to make progress when you reach low levels.
From your statement you wouldn't trade where you are for Adaptive Therapy, I am guessing you were able to go through the treatment with minimal AEs. TLS especially at the beginning seems to be a big worry, infusion risk with Ob is also a worry, plus you have hours of IV to sit through, neutropenia really worries me, as well as what happens after treatment -- that is, relapse recalcitrance.
I think it was in the appendix of the CLL14 study I saw that after treatment, doubling levels would return to a 45-90 day rate -- I'll have to pull that out.
But let me respectively ask the question a little differently based off those incredibly effective numbers you experienced: would you rather take a very low dose venetoclax for 1 day to lower ALC from 10 to 5, and repeat that once per year, hopefully forever, well, many years, than do the one year treatment to uMRD, knowing that you'll have a rendezvous with soemthing else in 3 years?
If you could keep the ALC between 5 and 10 with a low dose short term, even 1 day, treatment, one time per year, seems like a reasonable alternatives. Although I'll grant you, there are a lot of what ifs in there.
"A risk of TLS" shouldn't be a huge concern for many, when picking or starting a treatment IMO. "Not following recommendations to minimize or prevent TLS from occurring" is more of a concern. For example, TLS can occur with a BTK, and even happen spontaneously. The chances aren't as high, but it's possible.
I'm more about "how much monitoring is recommended, and am I able to get it & am up for doing it" in addition to "side effect profile" as well as "length of treatment." All are factors to be considered. Summarily rejecting a drug because it has a "higher risk of TLS" may not necessarily be a good thing. Unable or unwilling to get the monitoring? *That's* more the issue, no?
It's not fussed about which B-cells it kills, it does the lot. No B-cells mature into memory or plasma cells for a long time after. This has the effect of destroying the immune system for 6 to 12 months. Revaccination with PCV13 and PPV23 is recommended 6 months after treatment (13 months after last Obin) or when ALC > 1. There is a risk of TLS for those with high ALC. There are also common infusion related reactions on the first 10%+90% dose.
What it doesn't do is kill the CLL B-cells that are proliferating in the lymph nodes and bone marrow. It's really only effective on "dormant" B-cells in the peripheral blood. Over the course of the first 3 weeks with a 1000mg dose each week the lymph nodes do reduce, the number at high risk of TLS reduces from ~20% to 2%.
Venetoclax can quickly reach the B-cells in marrow and lymph nodes so the risk of TLS can remain after the peripheral blood has ALC <5. Peripheral blood is easy to measure, lymph nodes can be assessed by CT scan. Bone marrow biopsy is more invasive.
That is fascinating data Skyshark, thanks. I was under a misconception on venetoclax, thought that was the miracle drug. I checked the Clarity study, and they state that after leading in with ibutinab, which sometimes raises ALC by causing BM cells to migrate into the blood, when the venetoclax is added, there is a rapid drop off in ALC. Maybe rapid, but no where near as rapid as the nearly 2 orders of magnitude on a single day of Obi.
On obinutuzumab, seems killing the indolent B-cells in the peripheral blood would be a waste though, why would we care about those. Don't we want to focus on destroying the actively dividing cells in the BM and lymph nodes? Also, I know you were on a two drug therapy, but do you have any data on how quickly venetoclax reduces ALC count? Thanks again!
Skyshark, venetoclax can also reduce lymphocytes as quickly as obinituzumab can. It's incorrect to say otherwise, that it's only the MAB. That's why V has the TLS warning & risk assessment protocol.
Mine dropped similarly to yours within 48 hours on V. People died during the early V trials due to unexpected TLS. Now the monitoring protocol is rigorous, to prevent it.
When people choose a V&O protocol, by the time the O has done its thing, the TLS concern for the V is usually moot, since the O has already drastically decreased lymphs. TLS risk is now low, so intensive monitoring isn't recommended routinely when the V is added. People with certain co-morbidities & how their treatment is going, may still warrant intensive monitoring.
But those using V in ways where it's given first, or in the new V&I or V&A protocols when lymphs haven't yet dropped significantly, the TLS assessment & recommended monitoring should be done. As was done when I did V monotherapy.
Here is a hypothetical. I will use you as an example. You start taking Venetoclax when your ALC hits 15 and take it until your ALC is 5. You do this 5 times in 3 years. After 3 years, your doctor tells you that your CLL is resistant to venetoclax and you need to start a BTKi. If you had done Watch and Wait and V+O, then you would have been in Watch and Wait for 3 years and had a 5 year remission after you finished V+O. By doing adaptive therapy, you became resistant to Venetoclax 5 years earlier than necessary. There are hundreds of studies that show that Watch and Wait is more effective than starting treatment early. You are proposing starting treatment early which starts the process by which your cancer becomes resistant to Venetoclax (or a BTKi) early. Due to the fact that there are still only two types of treatments for CLL, starting CLL treatments years early can reduce your life expectancy.
To add to your hypothetical, combination treatments make it difficult for resistant clones to develop, because for a sub-clone to become established, it needs to concurrently develop resistance to each treatment drug. Theoretically, that means that as long as resistance doesn't develop, combination therapy can be repeated each time remission ends. This approach was used for the older chemoimmunotherapies such as BR and FCR and it was reasonably effective, particularly considering that the chemo component worked by deliberately introducing DNA damage. Remissions became shorter and eventually ineffective as treatment induced 17p del, TP53 and ATM mutations accumulated.
Thanks PennyLane and AussieNeil. PennyLane, you make a very good case, and is pretty much what the oncologists have been saying. But AussieNeil offers an excellent way to mitigate the problem of resistance by using a 2 drug approach:
"Theoretically, that means that as long as resistance doesn't develop, combination therapy can be repeated each time remission ends."
And I also want to note that the newer drugs don't damage the DNA like the older chemo did, so hopefully the mutation rate remains low, as consequently, resistance.
So let's change the hypothetical. Say you use a 2 drug strategy, venetoclax at the starting dose, 20mg, and ibrutinib at half the starter does, 200 mg, daily, and then monitor ALC, daily. Stop when you've hit a 50% reduction, say 15 to 7, anytime in the first week, and if not achieved in the 1st week, increase to 50mg and 400mg in the 2nd week.
Again, the idea is from Gatenby, disturb the microenvironment as little as possible, short term low dose keeps the AE down, the dual drug approach keeps resistance down, and everytime you cut the ALC in half, given the doubling time of a year doesn't change, you bought another year.
Thanks again for the input, I'm grateful your thoughts.
Even certain monotherapies may be redone, if a remission is deep enough/long enough. I am told I can repeat V monotherapy if I choose. I know my clone is starting to grow again, but it got tamped done so thoroughly by my treatment and somehow it seems to be growing back much slower than previous times I've "come out of remission." My specialist has said he will consider retreatment of a previous protocol, and the consensus at this point in time seems to be if a patient gets around 2 years without major problems, simply retreating won't be excluded from the next round of treatment options. I've been pretty stable other than an AIHA that turned out to be drug related not CLL related, and my other cell lines have maintained their "usual" if not improving. I've only had 1 infection in 2 years, i stead of my usual "yearly infection" and I think this last infection a few weeks ago was preventable. It was not cleaning properly after an elderly dog having accidents, getting feces & urine on our seating areas I was unaware of initially, that I am convinced caused the infection after an insect bite or a scratch that broke the skin.
Unfortunately (TMI warning) the wound was on my rear end & I sat on contaminated couches. Yes, there was severe, intense "discussion" about someone not cleaning up after their dog as asked to, which I am convinced resulted in the infection. Had I know the cleaning I requested wasn't done, I never would have sat in literal crap. So IMO the infection wasn't so much my impaired immunity, as unusual exposure to infectious agents. Who refuses to clean poop from their dogs' rear, which is sticking to excess hair there because the requested trimming of the sanitary areas wasn't done, and diapers were not put on properly so feces-laced urine was all over the couch, loveseat, and bedding? Ugh. Oh well, the bed is now clean & I am staying in that room until everything else is. At least I have a comfortable place with a nice view out the window, of mountains & birds. After the past few weeks of how the US weather has affected so many, I feel very blessed to have a safe spot.
yikes, sorry to hear about the dog incident, but still, this is actually valuable information, especially about the mono therapy.
Seems like resistance to venetoclax must not arise too fast if your using it as a mono therapy, and then again using it as a mono therapy. And since you had a deep remission, it must have been used over a relatively long period.
It makes me think, if you used venetoclax for a limited duration like a week or two once per year, for a shallow (vs deep) remission, the likelihood of resistance would t be too high.
But even so, as AussieNeil pointed out, provably better for a two drug approach.
Many of us don’t have the luxury of living in the world of hypotheticals. We need second and third line treatments. We are anxiously waiting to find out if FDA approves acalabrutinib + venetoclax or sonrotoclax + zanubrutinib. This would be a life saver.
I completely appreciate that, and we are lucky to be living in a time with such effective drugs coming down the pipe. But the point of the hypothetical, I hope, is to explore the possibility of a protocol for patients avoiding the need for 2nd and 3rd line treatments. Wishing1202 below mentioned real world results that seem to confirm the approach: “low and slow.”
I find this interesting because I spoke with a coworker who already had CLL when I was diagnosed. She was given two options from one local oncologist and one from a research center. The research center wanted to hit it hard and knock it out; the local oncologist wanted to go low and slow. She was in a group forum and kept in contact with those who decided to hit it hard to knock it out; she chose low and slow.
All of the patients who hit it hard, died within a year; she is still living 13 years later.
Wow, thanks Wishing, that’s exactly the point of Adaptive Theraoy. I didn’t know anyone had tried the low and slow approach for CLL. I would love to reach out to the oncologist who has tried this, can you let me know the doctor’s name or refer me to any papers they may have written. I’m stunned. Thanks so much for sharing this.
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