Adaptive Therapy Dosing Help

[PulsedTherapy]

Hi CLL Community,

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.

[cujoe]

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

moffitt.org/research-scienc...

moffitt.org/newsroom/news-r...

Good luck and very good health to you,

Ciao - cujoe

[PulsedTherapy in reply to cujoe]

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)."

scientificamerican.com/arti...

[cujoe in reply to PulsedTherapy]

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.

Stay Safe and Be Well, Ciao - cujoe

[PoisonDwarf]

Hi PulsedTherapy,

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.

[PulsedTherapy]

Hi PoisonDwarf,

Check out this link, it describes the Adaptive Therapy very well.

scientificamerican.com/arti...

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."

[LeoPa in reply to PulsedTherapy]

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.

[PulsedTherapy in reply to LeoPa]

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.

[LeoPa in reply to PulsedTherapy]

If it's only as good as obtaining uMRD I'm all for it. It doesn't need to be better 🙂

[PulsedTherapy in reply to LeoPa]

Yes, I think that is the point. If you can keep the lymphocytic cells from crowding out the other blood cells and stopping the cells you need from dividing, and keep the lymphocytic load low enough so you don't have lymphatic enlargement, it's largely a controlled asymptomatic disease.

However, mutations can always occur that become more aggressive. And while keeping the microenvironment intact, and leaving in place clonal competition, and cellular competition, you hope keeps the current clonal populations in check, those populatons are still large 10e9, rather than 1e4, for instance.

And a bigger population of cells itself can increase the risk of an aggressive mutation occurring just by the numbers. More cells to divide, more chance of an aggressive mutation. So, like everything, there are many factors that come into play.

[LeoPa in reply to PulsedTherapy]

Yes, one needs a lot of luck to live a long and healthy life. Doing all the right things is not always enough. But that doesn't mean we should not do them! To worry only about stuff we can do and influence and not to sweat the rest. That's the stoic way.

[PulsedTherapy in reply to LeoPa]

Nice, an Epictetus fan, couldn’t agree more.

[PoisonDwarf in reply to PulsedTherapy]

Thank you for the article, appreciate it. Intuitively the logic of this makes sense so we are in agreement, it's not a crazy idea.

My only observation was that convincing doctors to consider a treatment option that deviates from accepted practice is not going to fly. I say this because I have tried, it's not that I think I'm special or I have discovered some new option that medicine has missed, the evidence is there, but I don't yet meet the iwCLL criteria for treatment, so what I was proposing has not been tested and proven, so it makes it a no go area. It was like banging my head against a wall. I had to change my approach to 'pick your battles girl' for my own sanity. I now joke that science will eventually catch up with my body!🤦‍♀️🤪

I empathize with your frustrations, I went as far as examining my own motives for wanting to pursue early treatment. I went from cognitive bias creating blind spots, to sheer bloody mindedness & me needing to be right. I had a therapy session to re-examine my trust issues with certain doctors; a surgical oncologists actions had a judge promising me jail time for contempt of court, if I didn't sort him out.

As an aside, not off on a tangent! Our hands & face are what humanizes us. How often do doctors hold our hands, unless medically required? It intrigues me that when a doctor holds my hand(s) they realize how small framed I am. Does holding a hand make them see us as an individual, rather than simply another 'patient'?

Relating to the above, carpal tunnel is now recognized to be related to size, it's not just a repetitive strain injury, a neurologist & a surgeon tell me I was always prone to this. Updated guidelines have been been adopted in my area for treatment of iron deficiency and/or anemia, a rheumatologist explained a couple of anomalies in my bloods as normal ranges being based on population sizes. Over the prior 3 years, none of the doctors would give any truck to my size. It will be interesting to see the next response as a physio has recommended I bring up thoracic outlet syndrome.

Like you, it has nothing to do with any disrespect of my doctors. I still believe the best medicine is evidence backed. However, there is also evidence that well informed patients involved in their own care can have better outcomes. I have lived in & managed this weird body of mine a for lot of decades.

I really do wish you every success. You believe this is a viable option that could work for you, if you find a willing doctor and it is proven to reduce the risks of resistance & mutation, it opens up additional treatment regime for other CLLers. A number of the newer treatments were also first tested on solid tumor patients & due to their successes this subsequently opened up trials for CLL patients.

Time will tell.

Sorry for the essay. You may see no relation to your circumstances, so this is irrelevant! In that case, I'll say thanks for providing a safe space so I can articulate my thoughts.

Best wishes.

[PennyLane2024]

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.

onclive.com/view/fixed-dura...

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.

[PulsedTherapy in reply to PennyLane2024]

Thanks PennyLane, profile updated.

"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.

Thanks so much for your thoughts on this.

[SofiaDeo in reply to PulsedTherapy]

"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?

[Skyshark in reply to PulsedTherapy]

It isn't Venetoclax that has the remarkable and rapid reduction in ALC. It's the anti-CD20 monoclonal antibody Obinutuzumab.

Mine went from ~120 to <7 in 3 days, ~12 after the first 100mg (10%) dose.

The usual treatment is 8 doses of 1000mg over 6 cycles.

researchgate.net/publicatio...

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.

[PulsedTherapy in reply to Skyshark]

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!

[SofiaDeo in reply to Skyshark]

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.

[PulsedTherapy in reply to SofiaDeo]

Thanks SofiaDeo, I was definitely confused by SkySharks statement on Obi vs Venetoclax. I really appreciate your sharing your experience.

[SofiaDeo in reply to PulsedTherapy]

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.

[PulsedTherapy in reply to SofiaDeo]

Thanks SofiaDeo, the venetoclax is ramped up from 20mg to 400mg. Do they see TLS at the lower dosages?

[SofiaDeo in reply to PulsedTherapy]

Yes, it's whatever the tumor loads are at the start of any treatment, regardless of dose. I had massive die off & spleen emptying with my first two 20mg doses.

If one is doing V&O, much of the tumor load is usually gone by the time V is initiated. But I imagine, if for some reason one still had massive nodes & ALC over 25K, the "high risk" monitoring would be followed.

[PennyLane2024]

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.

[AussieNeil Partner Administrator in reply to PennyLane2024]

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.

Neil

[PulsedTherapy in reply to AussieNeil]

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.

[SofiaDeo in reply to AussieNeil]

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.

[PulsedTherapy in reply to SofiaDeo]

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.

Thanks, and keep those dogs off the couch.

[SofiaDeo in reply to PulsedTherapy]

It's not that "resistance is less likely since I was able to do a solo V treatment", it's this was chosen specifically for a number of reasons & I am aware of the risk I took. My specialist recommended V&O, it was *me* behind the "solo V" thing.

Currently, there's no way to know up front who will respond, how quickly, and whether or not resistance develops, and how fast that occurs.

It's funny, I guess I am actually doing an Adaptive Therapy approach, although I didn't know that term. I spoke with my specialist several years ago about tamping the disease down, getting a drug holiday, then repeating the same treatment, as an approach to managing the growth instead of shooting for a cure. I spoke of "keeping the disease burden low such that I could function relatively normally" instead of doing treatments that had more side effects & would suppress my immunity even more. So he approved the solo V. After a year, we checked residual disease, and the number was low. After a second year, that number hadn't really changed. But I went off the drug even though I hadn't reached deep remission (one person here, on a study, commented it took 5 years for them to reach deep uMRD on V, and they didn't get resistance). This December, it's Year 2 since stopping the drug. The plan is to see what percentage of lymphocytes are defective, doing Flow Cytometry. Then a decision what to do will be made after those numbers come back. My lymphs are now low normal, but even though they have grown a bit I am not having severe B symptoms. My recent skin infection was a freak thing IMO, I think if my partner had scratched his skin he also would have gotten an infection from his refusal to clean up after his dog. Not that I got a skin infection because my immunity is still extremely suppressed, and any skin break would have gotten infected.

[PulsedTherapy in reply to SofiaDeo]

It's great that you have "low residual disease" and it seems to be holding. I'd say the Adaptive Therapy approach though is to maintain a pretty robust disease level, it is the competition within clonal populations that helps keep the resistant clones in check. The link you sent to Gatenby's 2009 NIH paper really spelled it out nicely.

[PennyLane2024]

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.

[PulsedTherapy in reply to PennyLane2024]

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.”

[SofiaDeo in reply to PennyLane2024]

You don't need FDA approval to try V&A, just a doc willing to prescribe & an insurance or other ability to pay for the drugs.

There are a number of cancer protocols in use, that the drug companies didn't apply for & pay to get "FDA approval". Clinical research validating treatment is safe & effective as current treatments, is generally enough for insurance to pay. If ASCO makes a statement about how studies have shown "combo Y&Z" is efficacious & safe, and thus recommends it, many insurances in the US will authorize. Without FDA approval.

An analogous example, is that cisplatin mixed in a bag of saline solution is stable at least 30 days. Numerous stability & microbiology studies have shown this. So if a patient is expected to have a cycle, and the treatment gets held for some reason, their bag of cisplatin gets stored in the fridge until next month. It doesn't get wasted. Unless their weight has changed significantly, the bag isn't tossed, it's used the next appointment. Back when cisplatin wasn't generic and only 1 company made it, that company didn't apply to the FDA to get the storage requirements changed on the drug monograph, it's costly. There was enough data such that this "saving the bag for next month" was a practice standard. No FDA approval needed.

[Wishing1202]

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.

[PulsedTherapy in reply to Wishing1202]

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.

[MisfitK in reply to PulsedTherapy]

Low and slow is different than adaptive therapy.

Low and slow means trying the smallest possible med dose needed, but taking it consistently as prescribed, thereby getting your bodily system over the initial inflammatory bump and letting the med do its work over its proven course. I subscribe to this theory of "less is more."

Adaptive Therapy seems to be upheaving the system with larger dose therapy (2 or more to prevent resistance) and then pulling it back right as you'd get used to it over and over. This seems like an inflammatory nightmare to me.

But inflammation and I are not friends. If you lock this post, I would say more (it's under the edit function).

[PulsedTherapy in reply to MisfitK]

Hi MisfitK,

Thanks for you comment, when you say:

"Adaptive Therapy seems to be upheavaling the system with larger dose therapy (2 or more to prevent resistance) and then pulling it back right as you'd get used to it over and over. "

I am not sure that's completely correct. The idea is low dose short term treatment only to bring the ALC down a modest amount, for instance 15 to 7. Others have posted that they have treatments, which all start out with low doses to minimize TLS, and they've seen counts go from "120 to 4" in one day. So it would seem, you need very low dose and very short term treatment to make this modest decrease. The idea of a 2nd drug is NOT to kill more lymphocytic cells, but just to reduce the chance of a mutation occurring, because that mutation would have to provide resistance to 2 drug mechanisms and not one.

Here is Dr Gatenby's 2009 rationale on Adaptive Therapy:

"Initial mathematical models find that when resistant phenotypes arise in the untreated tumor, they are typically present in small numbers because they are less fit than the sensitive population. This reflects the "cost" of phenotypic resistance such as additional substrate and energy used to up-regulate xenobiotic metabolism, and therefore not available for proliferation, or the growth inhibitory nature of environments (i.e., ischemia or hypoxia) that confer resistance on phenotypically sensitive cells. Thus, in the Darwinian environment of a cancer, the fitter chemosensitive cells will ordinarily proliferate at the expense of the less fit chemoresistant cells. The models show that, if resistant populations are present before administration of therapy, treatments designed to kill maximum numbers of cancer cells remove this inhibitory effect and actually promote more rapid growth of the resistant populations. We present an alternative approach in which treatment is continuously modulated to achieve a fixed tumor population. The goal of adaptive therapy is to enforce a stable tumor burden by permitting a significant population of chemosensitive cells to survive so that they, in turn, suppress proliferation of the less fit but chemoresistant subpopulations."

I would love to hear more about your experience, but I couldn't find the lock. And if I lock, does the whole threat get locked? I am finding tremendous value in the thoughts of the community. There are really wonderful people on this board.

[MisfitK in reply to PulsedTherapy]

If you edit your post and look at the bottom, you'll see an option to have the post to be shown to anyone (ie - the whole internet) or this community only. You want to select this community only if you want folks to share their personal experiences. You know it's locked to the community when you see a literal lock symbol up by the subject title.

[PennyLane2024]

In order for your hypothesis to be true, we need to believe that thousands of CLL specialists and pharmaceutical company researchers are involved in some type of conspiracy against Adaptive Therapy for CLL. Many of these smart folks are actively involved in running trials that might allow us to be on drugs for shorter periods of time. That sort of is adaptive therapy. Right? The most logical reason that the Adaptive Therapy you are recommending isn’t in trial is because a decade of trials has shown that it won’t work. I will certainly speak to my doctor in a few weeks and see what he thinks.

[SofiaDeo in reply to PennyLane2024]

Well, I don't know about the conspiracy thing. From my understanding of how cancer treatment first evolved, it's been treated more like an infection; stamp it completely out. If people are questioning this basic supposition, especially for the "chronic" cancers that really can't be eradicated as easily as cutting out a solid tumor that hasn't metastasized, IMO it's a normal evolution of thought. We "manage" other chronic diseases like diabetes if changes in weight, diet, & exercise don't flip the numbers back to normal. Why not "manage" a "chronic" cancer, since eradication seems to be hard to do?

Just because no one has thought to run trials like this, doesn't mean that it won't work. Other trials weren't designed to show "is adaptive therapy better than this other therapy". The trials generally asked "is this therapy effective" or "is this therapy as effective as another therapy."

Since the Adaptive Therapy question wasn't asked, you just can't assume an answer. You Cannot Extrapolate Data to form a valid conclusion. You can extrapolate to consider a theory/question, but there's generally no information to give an answer.

[Stamphappy in reply to SofiaDeo]

I agree with you, SofiaDeo. "You Cannot Extrapolate Data to form a valid conclusion. You can extrapolate to consider a theory/question, but there's generally no information to give an answer.". I haven't heard of Adaptive Therapy, but I do find this a very interesting thought and conversation.

[PulsedTherapy in reply to PennyLane2024]

Thanks for the thoughts, but no, no, no, I'm am not calling for a conspiracy here. And there have not been trials that failed. Gatenby has been have great success with it with solid mass tumors. The roadblock is, it is completely counter-intuitive. With cancer, the idea has always been to eradicate it. Who can possible argue with that? And also, with drugs, you worry about resistance. Who can argue with that. Well, Gatenby makes the case and has been showing its efficacy. Be sure to read this, it's short:

pubmed.ncbi.nlm.nih.gov/194...

[AussieNeil Partner Administrator in reply to PulsedTherapy]

As you quoted from that reference from Cancer Res. 2009. That's 15 years ago - during which we have seen a transformation from "chemo" treatments for CLL to inhibitor treatments, which don't damage CLL DNA.

'The goal of adaptive therapy is to enforce a stable tumor burden by permitting a significant population of chemosensitive cells to survive so that they, in turn, suppress proliferation of the less fit but chemoresistant subpopulations.'

To continue that quote;

'Computer simulations show that this strategy can result in prolonged survival that is substantially greater than that of high dose density or metronomic therapies. The feasibility of adaptive therapy is supported by in vivo experiments. [Cancer Res 2009;69(11):4894-903] Major FindingsWe present mathematical analysis of the evolutionary dynamics of tumor populations with and without therapy. Analytic solutions and numerical simulations show that, with pretreatment, therapy-resistant cancer subpopulations are present due to phenotypic or microenvironmental factors; maximum dose density chemotherapy hastens rapid expansion of resistant populations. The models predict that host survival can be maximized if "treatment-for-cure strategy" is replaced by "treatment-for-stability." Specifically, the models predict that an optimal treatment strategy will modulate therapy to maintain a stable population of chemosensitive cells that can, in turn, suppress the growth of resistant populations under normal tumor conditions (i.e., when therapy-induced toxicity is absent).'

Importantly, chemotherapy research got its start in leukemia rather than solid cancers, because it is so much easier to monitor changes in the response to treatment, including any development of sub-clones. It's far easier and much safer for the patient, to take regular blood samples than take solid tumour biopsies.

Why not put your question about Pulsed Therapy research to the CLL Global Research Foundation? cllglobal.org/

Neil

[PulsedTherapy in reply to AussieNeil]

Yes, 15 years ago, and with a completely different types of drugs, but I am not sure that lessens the argument. And subsequent to this, Gatenby has shown reasonable success in patients. Here's one article, elifesciences.org/articles/... . "Improved time to progression and overall survival.'

Thanks for the link to CLL Global, I didn't know of it. I went to the page, I didn't see any forum for asking questions, did I miss it? Or should I just email it to the general contact link?

Thanks AussieNeil

[AussieNeil Partner Administrator in reply to PulsedTherapy]

That 2022 trial was a very small with 17 metastatic castrate-resistant prostate cancer patients.

With respect to CLL Global; per their website:-

Contact Us

Thank you for your interest in the CLL Global Research Foundation. The quickest way to communicate with us is via email. Please complete the form below to contact us or to register for email updates.

cllglobal.org/contact-us/

[PulsedTherapy in reply to AussieNeil]

All set, sent this:

Possible trial for CLL using Dr Gatenby's protocol for Adaptive Therapy. The idea is not to use MTD to achieve uMRD, but instead treat CLL chronically. Only use low dose drugs for short durations to scale back lymphocytic cells so it doesn't interfere with other cell production, eg. platlets, RBC, neutrophils, with the possible advantages that:'

1) less AE

2) lower drug costs

3) lower chance of selective pressures for a resistance clonal population

4) less alteration of the microenvironment so signaling stays stable, clonal and metabolic competition stays in place that limits new mutations and proliferation

Here's a hypothetical trial:

1) patient has ALC 10e9, asymptomatic, doubling time 1 year

2) treat venetoclax and ibrutinab at low dose, 20mg and 200mg, daily, testing CBC each day, and stopping the drugs when ALC hits 5e9, half.

3) all else equal, this should buy the patient a year

4) when ALC hits 10e9 again, repeat

Here's a great overview to Gatenby's idea (link below), who I spoke to, and says he sees it reasonably likely this protocol can cross over from solid mass tumors to CLL because CLL replicates in the BM, not the peripheral blood, which is similar to solid mass tumors:

scientificamerican.com/arti...

He also has many papers of his work that show promising results, here's one:

elifesciences.org/articles/...

Thank you for your important work in CLL

[SofiaDeo in reply to PulsedTherapy]

IMO part of the problem in treating CLL, is that there isn't a great deal of correlation between "levels of lymphocytes" or "size of nodes" and "other important cell lines (neuts, platelets, RBC's)" plus "immune globulins". We need to treat mostly based on things like how the other cell lines and immune globulins are affecting things lime anemia, thrombocytopenia, neutropenia, actual number of infections; not lymphocyte count.

And our treatment guidelines have more variables than, say, prostate cancer. So there are more things to juggle and it's difficult to determine exactly what dose "generally works" because just lowering lymphocytes may not correlate with improvement in any of the monitoring/treatment parameters. Docs (like mine) may be willing to modify protocols somewhat for relatively stable patients (like me; no neutropenia, excessive infections, severe anemia, etc.) but other patients not enjoying this stability, or those with SLL presentation where other organs can be/are affected by node size or tissue infiltration that doesn't correlate with decreased lymphocyte counts, may not qualify/this approach may not work well.

I do think it can be useful if whatever problems a patient has, actually improve with an adaptive technique. But if lowering lymphocytes modestly doesn't resolve other problems, this treatment type probably shouldn't be continued or considered unless/until the problems that actually triggered "time to treat" have resolved with continuous therapy/current standard protocols.

I wonder how often a Bone Marrow Biopsy(BMB) should be recommended with adaptive therapy; I would think one may be needed somewhere in there, to verify any patients who are like me. My "other cell lines" and nodes had yet to change out of normal range at my diagnosis; it was feeling ill, rapidly rising lymphocytes, and lymphs that looked a lot like blast cells had a BMB being done. My marrow was almost pure white, and was limely to fail shortly. So I was staged "zero" but started setting up treatment. In the few months it took to arrange to start my treatment of choice, those other cell lines started to be affected. My almost completely infiltrated marrow finally started to fail in the other cells.

If my lymphs had only been dropped to mmm half, my marrow wouldn't have been cleared out. Who knows if other cell lines may have been able to continue, if I wasn't clearing out my marrow just dropping blood lymphocyte level. So I wonder when/how BMB should be considered for people like me, I'm sure I'm not some sort of unicorn.

[PulsedTherapy in reply to SofiaDeo]

Excellent points SophiaDeo. Early treatment, if possible, may be able to avoid many of the problems with other cell involvement you are referring to. Keep the lymphocyte level below the threshhold where it starts to crowd out other cell production: RBC, platlets, neutrophils. And before the lymphs grow uncomfortably large.

Glad you mentioned BMB. I didn't realize that was such an invasive procedure, it's not a needle, it's a core. From some data I looked at, I don't see the need. There is always a correlation between PB and BM, so why do they need hard data on the BM?

Also, I'm not so sure they know exactly where the replication is occurring. Are all places in the BM representative? Can the replication be happening in the lymph nodes rather than the BM? Or different places in the BM. Just doesn't seem to this lay person the BMB provides much more information over PB.

And will it really be a factor in treatment, or is the PB proxy enough?

Certainly with the Adaptive Therapy approach, they'd be no reason for BMB.

[SofiaDeo in reply to PulsedTherapy]

There is not always a correlation between PB & BM infiltration. Using current protocols, there may be correlation *at the end of treatment* based on successful uMRD (I think it's like 98%, not guaranteed) but not at the beginning stages of this disease. I had almost complete marrow infiltration with lymph levels around 50,000.

How do you explain the varying levels of bone marrow involvement that do not correlate with lymphocyte levels? Some here have had varying levels of infiltration with the same lymph numbers in the blood, and the doc treas the marrow infiltration, not the blood number. What about SLL types who may not have many lymphs in blood at all? Those would likely need different monitoring, since node reduction is more important than blood tests.

ashpublications.org/blood/a...

ashpublications.org/blood/a...

emedicine.medscape.com/arti...

Early on (i.e. at diagnosis) the extent & type of marrow infiltration correlates with prognosis. It's not explicitly stated, but if lymph numbers *did* correlate with marrow infiltration, there wouldn't be a need to investigate marrow to make prognostic statements. One could simply look at the number of lymphocytes.

"The extent of marrow infiltration correlates with prognosis and stage and the diffuse pattern is typically associated with advanced disease."

ncbi.nlm.nih.gov/books/NBK5...

[PulsedTherapy in reply to SofiaDeo]

Did the data from you BMB differ enough from the PB that your treatment was altered? Seems that should be the threshhold question. I'm often surprised in the business, but to see a 10e-3 in the BM, for example, seems unlikely. And like you said, what do you do with the patients where replication is in the lymphs. And what lymph? This is my nature, to question everything.

[SofiaDeo in reply to PulsedTherapy]

With me having a BMB of almost pure white/almost completely infiltrated marrow, it was thought treatment was imminent because an almost completely infiltrated marrow is close to failure. That hem-onc had stated he had never seen marrow so white, The FISH & Flow results had not yet come back. That coupled with my physical symptoms of "feeling really ill" and lymphs that were overly large/more like blasts (classic CLL cells are small & round) had the doc initially assuming an acute process. The flow & FISH verified CLL; I had an extended FISH done because they weren't sure *what* I had with that unusual pure white marrow, and it's how it was discovered I had a complex karyotype. A standard CLL panel only tests for mmm 5? 6? genetic aberrations, I have 2 deletions on those.

So my treatment wasn't "altered" because back in 2011, with my genetics, the only option I was offered was a stem cell transplant. I wasn't offered FCR or BR as an option. I had had a series of tooth infections over the summer; as of September my WBC was slightly elelvated but late December it was around 50,000. This original workup was at a non-CLL specialist, regional hem-onc practice.

So I chose a clinical trial across the country. It wasn't available anywhere near me, only East or West coast larger institutions. That drug didn't work but did halt the rapid CLL lymphocyte growth, which lessened some of my symptoms. I was kicked out of that study, but since this was a research group they knew about the new monoclonal antibodies (MABs) that had recently come into use. I chose to copy a trial of one, ASCO had just come out with a statement that using this drug alemtuzumab moving forward should not be IV but subcutaneous(SC). Infusion reactions from the new MABs were something I didn't want to risk.

Back then the CLL MABs were relatively new, and practitioners weren't as experienced with dealing with rituximab or alemtuzumab infusion reactions. The practioners who were infusing the large molecules, notably Gamma Globulin, were ER and ICU specialists. Up until the MABs, oncology docs didn't really infuse large molecules often, so oncology wasn't really experienced at dealing with infusion reactions. I once had a situation on a hospital oncology floor, where an ICU patient *had* to come to oncology to get an immune globulin infusion, the ICU's were all full & no room in ER. And this was the days before step-down units. The ICU docs decided Oncology, which was right next door, was to be the place. The RN's consulted with me how to best do this & I helped monitor/make recommendations. It was only a few hours until that patient could be moved to an ICU, but that patient almost crashed, had numerous rate adjustments, and the RN's were really stressed because this was out of their wheelhouse, especially without cardiac monitoring equipment. So I really didn't want to be an early guinea pig & risk an infusion reaction.

The drug I used SC, alemtuzumab, commonly had severe infusion reactions and much more immune suppression than rituximab (it affects both B and T cells). Other MABs were trialed even though they didn't go to market, or went to market for different diseases, and research staff grew experienced with MAB infusion reactions. But back then, patients often crashed & got admitted. I wasn't comfortable doing a MAB infusion at that point in time.

So when obinituzumab was approved, the fewer/less severe but still present infusion reactions were noted carefully & protocols developed to deal with them successfully. If my life situation had been more conducive, I would have done the V&O as recommended. But it wasn't and I didn't.

I've been in trials since where my lymph count was well over 100K, and I'm sure I didn't have excessive infiltration with this "near white" bone marrow again. I've related this experience to my current specialist, and while I've never asked exactly what percentage infiltration I've had when getting a BMB for a study, I'm confident if it occurred again someone would have mentioned it. This particular clinical research group & I have fairly detailed medical discussions with me, and since it's considered unusual to have almost complete infiltration, I think someone would have said so.

But I think I am going to ask next visit, I'd like to be sure now that it's in my mind again!

Re:the SLL question, since the "usual" is to have a CT to count & measure nodes, I wonder if this would be continued. I think having numerous CT's isn't particularly wise unless warranted, and wonder what number of CT's would make the more numerous times one got radiation exposure be riskier than just doing an oral treatment with possibly only a yearly CT.

Perhaps once we get some decent data around the current studies looking at "stopping the drug once reaching uMRD", how quickly one reached uMRD, and the corresponding length of remission, this type of data may result in adaptive therapy trial recommendations. And then someone will successfully write a trial proposal & get funding to study this.

[OldProf24]

no expert. But I have CLL and take Calquence daily. My dad had CLL 25ish years ago (passed away 10 years ago) and back then they waited (as they did with me…until a blood transfusion was required due to low red cells where for him his white cell could for too high (mine was only 35-40..his was 160+)). For home they did an RFC treatment he got 5 years from that..then did a 2nd treatment…within a couple of years of that 2nd round he was needing help and they tried again but couldn’t complete the series. So I always did wondered why they just didn’t try staying with just Rituzan he tolerates so well to just beat it back as you suggest. Sounds like the daily calquence is giving people a longer symptom free period than he got….though my doc said there is currently research to evaluate if taking a break from Calquence was better. So far every day works for me.

[PulsedTherapy]

Thanks OldProf24, the strategy does have its appeal. Gatenby told me engineers seem to have a real preference for it. The point with adaptive therapy goes further than the daily Calquence, which I suspect is bringing a pretty decent remission. That is, a low ALC. The point of Adpative Therapy, is not to bring the lymphocytic population very low at all. But instead, just low enough so you can live relatively asymptomatically, and let the different clonal populations keep themselves resistant populations in check.

[PennyLane2024]

Pulsed Therapy should refrain from making claims about Adaptive Therapy until he can present us with a scientific article from a peer reviewed publication that presents data that adaptive therapy can work with CLL.

[PulsedTherapy in reply to PennyLane2024]

I make no claims. I am just presenting this new idea proposed by Dr Gatenby for CLL to this community that is so knowledgeable to (1) better understand its potential and to (2) let other people know that an interesting counter-intuitive alternative has been having success in solid mass tumors. I did contact Dr Gatenby, and he said it was reasonable to think there could be an application to CLL because replication happens in the BM rather than the blood, which resembles the environment of a solid mass tumor.