uMRD is great, but for a majority that reach it, CLL will inevitably reoccur, and at that point, because of the strong selective pressures put on the surviving CLL cells, they become refractory (unresponsive to treatment).
To achieve uMRD, therapies take a "long" time and the longer the treatment the greater the selective pressures for mutation and the extended period of neutropenia (suppressing your immune system) creates an opportunistic environment for other diseases, especially secondary malignancies.
Interestingly, in CLL, the CLL cells themselves aren't a problem until they start crowding out other cells creating cytopenias, low platlets, low RBCs.
So my question is this, why wouldn't a short pulsed approach be a reasonable treatment strategy?
Let me give an example, in a patient with an absolute lymphocyte count of say 10E9/L that is increasing slowly, treat with a 4 week course of Venetoclax (which works incredible fast), not to uMRD, but to lower absolute lymphocyte count to 1E9/L. At that point, go back to wait and see, repeating when the level increases to the 10E9/L level again.
The point of this is to limit the extended period of neutropenia and other adverse events, as well as secondary maligancies, and especially to avoid placing selective pressures on the remaining CLL cells that select for refractory mutations.
Of course, it is a very valid point that a 4 week course of treatment, repeated, say annually, also places selective pressures. And that is true. But mutations take time. I'd think a year plus course of treatment would have a much greater chance of a mutation getting a foothold than a 4 week course.
Also, the CLL cells as well as normal cells, are in metabolic competition. If you reduce the CLL count to a very low number, and those CLL cells left, which are likely to have survived by selective mutations, and exist at least on the order of 1000, would have an excellent environment to grow and divide.
By keeping 1e9/L cells around, there will be increased metabolic competition, and with the Venetoclax removed, there would be limited selective pressures for those that had mutated to preferentially survive.
I have no special knowledge, just a thought after thinking about CLL for awhile. I would love to hear anyone else's ideas on this, even if you want to say this all wrong and the worst idea ever. And it might be, but would appreciate your feedback.
Thanks for reading.
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PulsedTherapy
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You have a false assumption. You are assuming in the time period if the blood level of CLL decreases, it also decreases in other organs, spleen, nodes, marrow, etc. You're assuming some sort of linearity, in addition to the nature of the disease. There is no evidence that CLL acts like this; in fact, it's the opposite. That's what a "heterogenous" disease means. Your assumption may possibly hold if CLL was homogenous, but it's not.
A diagnosis of CLL is sort of like saying "heart disease." It describes a general problem. "Chronic abnormal growth of lymphocytes." The specifics of the cause of the problem, and how it's best treated, can vary.
If this assumption were true, how do you explain an SLL presentation? How do you explain people who fail on venetoclax? Or some people who reach uMRD in 2 years, with others taking 5 years on the same drug?
I agree that my simple example regimen is certainly not for all cases. Especially like you point out, how different the course of the disease can be.
My main point though, discontinuing a therapy long before you get to uMRD to decrease the chance of resistance still may be credible.
I took the liberty of reading your very well done bio, and I wish you all the best in your fight against CLL, and you seem to echo my main point when you write:
“Repeat uMRD by blood instead of bone marrow in Dec 2022, showed the 12 CLL cells per million still there. I wanted a drug holiday, plus, I was concerned about potential Venclexta resistance with a monotherapy, so the drug was stopped.“
Mmmm I see your point, but I don't think merely stopping the growth a tiny bit is enough. At least some researchers liken cancer resistance to antibiotic resistance in terms of the evolutionary mechanisms. An argument in favor of this, is how people used to eat small amounts of arsenic; those people could then ingest larger amounts without it killing them. Short bursts of antibiotic exposure, nowhere near enough to almost exterminate it, is the commonly agreed mechanism that allowed bacteria to become resistant to antibiotics. It is assumed cancer would act the same way. You need to severely tamp it down. The issue then becomes, what is the minimum amount of time we can tamp the cancer down, without risking more damage to the other parts of the bone marrow?
If one has a pustulant wound, you drain ALL the pus, you don't just remove a small amount. If one has a solid tumor, you try to remove ALL of it, not just some. Same for CLL, I think. 2 years versus 5 years on a drug is a different thing in terms of resistance, compared to only a few months. Repeated extremely short term exposure drives antibiotic resistance, and there are complicated equations showing why the evolutionary forces make this so. It's similar in cancers, I have read. You want to smack down the cancer as much as possible, without beating up the marrow or other organs too much.
Thanks for you reply, I appreciate it. And I can't find much fault in it, you make a valid argument. It comes down to a numbers game, and I'm struggling to find the right ones. I will say though
(1) in a solid mass tumor, there is a good chance, at least in many cases, you can actually get all of the cancer. That doesn't seem to be the case in CLL. The CLL cells are everywhere. 5E9/L times 15 liters of blood, is 75 billion cells, it's hard to get them all, even if there have been some spectacular success, but they are more the exception.
(2) in the bacterial analogy you give, the rates of bacterial replication are enormous, and usually accompanied with toxicity. The replication rates in a large number of indolent cases is much lower, and there is no toxicity. The worst of the pernicious effects of CLL is when they crowd out other cells from being able to do their function, cytopenias.
(3) also, bacteria generally don't have the proof-reading apparatus of human cells, so their mutation rate if much higher.
(4) "I don't think merely stopping the growth a tiny bit is enough" Couldn't agree more, a tiny bit is simply not going to do it. But this whole pulsed idea came to me when I saw the venetoclax results over time (I attached a jpeg from the CAPTIVATE study). You can see that a 1 month course of the drug has a staggering large reduction.
Thanks again for taking the time share your thoughts, I am grateful.
I agree, and think perhaps we are in agreement on the concept, but differ on the "relative numbers" or "time to get to those numbers." I am being told that current thinking is, if a treatment gives a reasonable remission for somewhere around 2 years, a repeat may be considered. A brief review of current ideas on theory of cancer evolution shows tumor cell plasticity may confer a resistance after even brief exposure. They don't have the characteristics that bacteria do, as you noted. So "fewer exposures overall" may be preferred/optimal.
Perhaps the studies looking at uMRD guided therapy will show the numbers that many patients with extremely responsive CLL, will need for "months after reaching uMRD" guided treatment. My understanding is that is what doctors are asking with these studies, "how few drug cycles can we give to reasonably expect a decent time of disease remission." So it's similar to your "pulsed" concept I think, with uMRD being used as the measurement. Perhaps some combination of markers only will need a uMRD4, while others may need a uMRD6 for varying lengths of time.
My fantasy is that this is true, and that my 2 year venetoclax treatment that got me to uMRD4 (similar to my almost 5 year remission) but not uMRD6, will give me a longer time before needing treatment, similar to that previous long remission. I never felt 100% back then, similar to how Indon't feel 100% now. My other treatments/docs didn't do a Flow Cytometry to test if I was negative by flow if I didn't have a treatment failure, so I have no way of knowing if I ever reached uMRD4 on other treatments except for that one.
This graph isn't for Venetoclax. It's for Venetoclax after 3 cycles of Ibrutinib have disgorged the CLL cells from the lymph nodes - this is the initial rise in ALC.
Bone Marrow - who knows? That takes longer and measured response by MRD4 is less deep. More patients had uMRD4 in blood than BM at end of cycle 15.
Thank you for including the jpeg from that study. I think that it demonstrates why graphs are beautiful but, carry a caveat like all statistical tools.
What took place historically is not guaranteed, to be repeated for the next time. It can show a trend, however it can over accentuate a biased desire. At the 4 month mark yes, there are very nice looking plunges, but at two months there's almost a uniform rise, small but by one's adjusting the scale of months to weeks, one could focus at the 8 week point and state an almost universal rise in the trend.
It is not unlike the predictive string models for the Atlantic Hurricane forecasts [CONUS], the general trend often is most accurate when one says, "Ah it will travel in a Northerly direction". After that, one is only watching and hoping in the end.
Hi PulsedTherapy and welcome to our community. It seems you've had CLL for some time to think this through, so perhaps you can share some of your journey?
You've proposed an interesting hypothetical means of possibly managing CLL, which is similar to how some patients had their CLL managed by regular rituximab infusions, though there was never a multi-armed clinical trial to see if it offered any advantages.
You say that "mutations take time", but I don't know how you determined that. Healthy B cells have been found to have a cell turnover of around 2% per day. ashpublications.org/blood/a... (Recall how quickly our neck nodes can swell from dividing lymphocytes when we are fighting off an infection.) If we assume a CLL doubling time of 2 years in someone just diagnosed with 5 x 10^9 CLL cells in just their blood, that's about 15 x 10^9 new CLL cells per year or 500 new CLL cells per second. Only one of those needs to have an error in its DNA to create a new sub-clone, resistant to venetoclax.
Also, keep in mind that venetoclax is a larger molecule than a BTKi inhibitor. Hence it's less able to penetrate our bone marrow than a BTKi, which is why these drugs work synergistically, with the 'brutinib' drugs driving the release of CLL cells from the marrow and nodes into the blood, where venetoclax makes short work of them. Which brings me to why haven't you proposed a short term combination therapy approach? That way any mutations need to be resistant to all the treatment drugs to survive. Even then, realistically, it's going to take several months to knock back the CLL so that it's at a low enough level to reduce symptoms to an acceptable level. So I think treatment for about a year, followed by hopefully a 5+ year remission/drug holiday would be far more acceptable, even if your proposal worked, which, if you think about it, is a half way approach between BTKi continuous therapy and fixed term combination therapies. I would have thought that CLL researchers would have tried this approach if it had any merit, particularly back when we had even faster acting chemoimunotherapy treatments like FCR and BR.
I agree with AussieNeil's observation, "I would have thought that CLL researchers would have tried this approach if it had any merit...". I think they did all the heavy lifting when developing these drugs in the first place, dosage, duration, etc.
SofiaDeo also, raises a good point about CLL/SLL being heterogenous. As I've examined the treatment flowcharts, the medical staff is trying to follow a standardized algorithm; to do otherwise (outside of defined trials), would allow for far to many variations and introduce uncertainty as to best practices in medical care. In addition, the expensive medicines, ordering them, actual procurement, and the increased time factor of medical staff per patient would lessen the quality and quantity of care.
That is not to say, you're thinking on different approaches is not refreshing PulsedTherapy. Perhaps, you could ask your specialist if they are aware of any trials that actually are aiming for this purpose.
I'd encourage you, as you are so new a member, to restrict your post to this community, and fill in your bio with the important medical findings about your form of CLL/SLL. You are obviously knowledgeable about the medicines, lab counts, and targets for disease treatment, and your screen name signifies a definite purpose.
Thank you Spark_plug, I will, and apologize for the bias screen name. I can see this is a fabulous site, with smart engaged users, and I will definitely be interested in more than just this nascent idea of pulsed therapy.
Oh, I wasn't chiding you about your handle. I only was impressed that you're synthesis of so much knowledge about CLL to proposing an approach in treatment didn't have more in your bio.
So, I was simply surprised, no apology needed, looking forward to your future submissions
I feel blessed to have found this site. So many thoughtful, intelligent, and kind people. I see you are a "Founder Admin," I am grateful for your efforts.
Thanks for the reply, it is thoroughly thought provoking. I'd like to address some of the very valuable insights you provided, again, I speak with no special authority or knowledge, and certainly feel free to consider anything I write more of a question than a fact (I don't want to take credit for that, I think Neils Bohr said it first, and no, I am absolutely not comparing myself to that great man).
"You say that "mutations take time""
1) CLL cells tend not to replicate faster than ordinary cells, but through apoptosis inhibition, they die much slower. Accounting for the amazing efficacy of venetoclax (and thanks, I did not know because it was a large molecule it was less effective in the BM).
2) The paper you reference was great discussing the kinematics of B cell replication. Because the replication rate in CLL cells is likely to be similar to ordinary B cells, I think the 2% daily rate is a good number to use for analysis.
3) I have always thought, as a rule of thumb, human genomic replication has a base pair error rate of 1 in 1E9. I would think it would be similar in CLL cells. The infamous TP53, tumor suppression gene, is not an error correcting gene, but rather an after the fact signaling protein to kick off apoptosis in defective cells.
4) the human genome is 3e9 base pairs (BP) long, so every replication comes with 3 defects. Of course most of the genome does nothing, although there is some very exciting new papers that talk about the importance of ncRNA (none coding), which may challenge this assertion. But let's just talk BCL-2, because that is a crucial area for a mutational change to confer resistance to Venetoclax. The BCL gene is only 230E3 BP long. The chance of one of the 3 random mutations actually being in the BCL gene is
Of course, just because you get a BP mutation in the gene, does not mean you will actually have a resistance causing effect. In fact, most BP mutations do little. But let's just leave at 4.e3-13 as a worst case.
5) The chance of a resistance conferring mutation will be a function of the number of days the cell can replicate.
#Res=(chance of res )*(# of cells/L)(L)(# of replication)=(4.5e-13)(5e9)(15)(1.02)^days
where I use 15 liters of blood to multiple by the standard 5e9 CLL cells/L
Here are the probabilities of a resistance causing mutation for various days
days calc # res cells
1 .03
30 .06
180 1.2
365 46
6) what I hoped to do here is using the kinematics from your paper to address my assertion that mutations take time, more specifically, it takes time for the right mutation to occur that will confer the resistance.
7) It can be argued, and rightfully so, that these mutations are taking place anyway. But there is a big difference. When the mutation takes place in an untreated environment, it is just one cell amongst billions, subject to all the normal metabolic and physical competition all the cells have. But when it takes place in the presence of venetoclax, then without competition, the mutation will take over.
So, to sum up, this is my logic in saying, minimize the course of the treatment only to control it, not achieve uMRD which takes a much longer course.
And if anyone is still reading (thank you), I'll address one other great comment
"Which brings me to why haven't you proposed a short term combination therapy approach?"
Yes, yes, yes. I was just giving a simple example to illustrate. But just like in HIV where they give a triplet of therapies for exactly the reason that there is so much replication, it will overpower the chance of one mutation, so you multiple drugs. This strategy could definitely apply to my pulse strategy too. I just presented it in simple terms with venetoclax because it works so fast. If this strategy was actually going to be tried, a combination strategy would seem entirely appropriate. It is interesting that AV and VO both show very high effectiveness, but adding a third, AVO, does not. That could be telling us that the mutation rates are not high enough to require a 3rd drug, like they do in HIV (and yes, one is viral replication vs DNA, but the principle here is the same).
Again, thank you so much for you comment and interest here. I look forward to any feedback you'd like to give
To my knowledge, there's no mathematical model of B-cell replication rate in CLL. Too many variables. So much of the discussion ends up like, "Could Batman beat Superman in arm wrestling" (Of course, Superman wins). It's fairly well known that untreated CLL will show accelerated doubling time, and the relapsed CLL progresses faster.
re: "The infamous TP53, tumor suppression gene, is not an error correcting gene, but rather an after the fact signaling protein to kick off apoptosis in defective cells."
TP53 may not fix errors itself, but it does also trigger other enzymes to fix errors, and stops the cell cycle to allow time for the repair. Repair enzymes can't fix all types of errors, though.
Errors can arise during mitosis (cell division), but also during transcription (copying DNA to RNA to later make protein). So genes that are transcribed more suffer more damage on average.
Several papers have observed in trials that the amount of time for significant Venetoclax resistant clones to appear is about 2 years. So the current 1 year V&O is not expected to select for resistance, and V can be used again. Meanwhile, the patient and their marrow are getting older, and perhaps some resistant clones have gathered numbers, so the second V&O (or V&R) series doesn't last as long. There have been Venetoclax monotherapy trials, but I haven't seen a comparison of V vs V&O and relapse. I'm sure it's there, and bet that V&O is more durable. But the question would be is V after V worse than V after V&O? I would expect so, because V by itself doesn't kill resistant clones like V&O would.
I would also note, however, that uMRD can be achieved by some patients after even 1 or 2 cycles of triple combination therapies. But the O in the triple comes with some infusion related reaction - which can be avoided to some extent by a few cycles of a BTKi before the first infusion. Sadly, that wasn't the case in the triple trial I'm in (pirtobrutinib, obinutuzumab, and venetoclax), and I had a nasty infusion related reaction. I and most others in the trial achieved uMRD6 by the end of Cycle 4. They didn't do MRD testing any earlier. My ALC was normal after a single week, though it climbed back to 7K a week later, and hovered just above normal for a few weeks. It went normal at end of Cycle 2 and stayed there ever since. I wish they had at least done Flow Cytometry MRD or Lymphocyte Subset Flow Cytometry at each cycle. By end of Cycle 4, CD19 was 0, and stayed there ever since. I'll be getting another ClonoSEQ and hopefully a lymphocyte subset this coming tuesday for my first quarterly followup.
I can see a time when a more gentle therapy allows treating sooner and prevents some of the quality of life issues we experience in W&W. But trials will need to be done. There's been a lot of talk lately about matching doses to the patient, too. The one-dose-fits-all approach is an issue in many types of cancer and chronic diseases, and requires doing Phase 1 trials in a different way - and with more volunteers.
I can certainly see a drug like pirtobrutinib being used much earlier than currently done, because it has so few side effects. It does have some, though, and we need better testing to identify who gets them and what can be done. Most of what's known about it is from R/R trials and the Phase 1 trials.
Your pulsed approach may merit investigation. But I think there will be other strategies pursued first. It takes at least a couple of years to get a trial off the ground. Finance is an issue, too.
Thanks Seymore, that was very informative. Congratulations on uMRD6, fantastic. Can I ask your TP53 status? Your post made me think about a couple of things:
(1) " They didn't do MRD testing any earlier. My ALC was normal after a single week, though it climbed back to 7K a week later, and hovered just above normal for a few weeks."
Amazing how quickly the VPO triplet worked. I thought it was odd the ALC decreased and then increased. Do you think this is because the PB is more responsive than the BM, and cells from the BM migrate back into the PB? In that way accounting for the drop and then increase.
(2) "But the O in the triple comes with some infusion related reaction - which can be avoided to some extent by a few cycles of a BTKi before the first infusion."
I've seen this elsewhere too. I'm surprised at this point, a BTKi initial course isn't standard practice.
(3) "I had a nasty infusion related reaction."
Wow, that sounds awful, glad you pulled through. If you feel like sharing, I would love to hear a first hand account of just how "nasty: infusion related reactions can be. Sounds pretty scary.
The more often we test, the less we can explain the ups and downs. How much was due to steroids with the Obin? How much due to Pirto clearing out the spleen and nodes? Blood tests are sometimes the drunk looking for his lost keys under the streetlight because it's easier. The keys are in the nodes, spleen, and marrow, and it's hard to do basic research there.
I posted details of my infusion reaction over a year ago.
Trials take a lot of planning. There are review boards. Changes in protocol have to be discussed and approved. I imagine the order of drugs was discussed, but it was too late to make the change.
Originally, the trial was supposed to be 7 total cycles, with MRD5 status determining an additional 6 cycles. It got extended to 9 cycles, and finally to 13 for all participants, with MRD5 determining an additional 13. I think the choice of MRD5 was based on other trials that use a more advanced Flow Cytometry MRD. The ultimate 13 cycles puts it more in line with some existing triples for better comparison. The original 7 cycles was an indication that they thought this combo would do significantly better than other therapies. Just as the trial was finally starting, Dr. Philip A. Thompson, a pionerring doctor, left MDA to move back to Australia. So there was a lot going on behind the scenes.
Combination therapy trials using targeted therapy drugs only commenced around 7 years ago, so keep an eye on long term follow-up reports, such as the CLL14 study of treatment naive CLL patients. A recent update of that clinical trial noted that "The 6-year follow-up results of CLL14 demonstrated the significant long-term PFS benefit of fixed-duration Ven-Obi across all subgroups of patients with previously untreated CLL and comorbidities. These benefits were maintained across high-risk groups, such as those harboring the TP53 deletions/mutations or IGHV unmutated, and over 60% of patients did not require a second-line treatment." (My emphasis)
I expect the BTKi/BCL2/CD20 triples will show even longer PFS. It's all been Phase 2 trials so far. I think there's a single AVO triple in Phase 3, but I can't find much about it.
The oldest that I'm aware of is the IVO trial at The Ohio State University, which started in 2015.
Updated Results from a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease
Blood (2022) 140 (Supplement 1): 837–838.
That trial just ended in March, and the study ends in September, 2026.
Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial
Lancet Haematol. 2021 Dec; 8(12): e879–e890.
That started the MRD driven triples, I think. Overdue for an update. I think it might have ended to quickly for some.
Hi I have had 6 years in Flair trial in the U.K. and moved to the static trial recently. On Static continuous verses intermittent treatment with ibrutinib is being researched. From what I have read here am I correct in thinking this is similar to the short term pulsed treatment regime referred here. Perhaps Aussie Neil could enlighten me here.
My UK co-admin @Jm954 posted about this extension to the FLAIR trial a year ago in this pinned post healthunlocked.com/cllsuppo...
bennevisplace quoted the relevant details of what the restart arm thus
Pausing ibrutinib: Take a break from ibrutinib and only restart if your CLL gets worse again, if restarting ibrutinib controls your CLL again, you will be able to take another break from it.
Continous ibrutinib: Continue to take ibrutinib every day. You will continue ibrutinib without a break as long as you are benefitting from it."
So repeating the intermittent treatment is based on when CLL becomes worse again and is not to a regular schedule.
Thanks for that feedback annMcGowan, That's very interesting that there is already a pulsed, or intermittent, trial in place. I will check out the Flair study. Just goes to show what I've often thought, it's nearly impossible to have an original idea. When you think you've thought of something, you find out someone else came up with it long ago. All my best.
Hi I wasn’t using any definition Seymour, I was asking a question, ‘does the static trial, I am on, fit the criteria pulsedTherapy was talking about. The criteria for static is not uMRD it is Clinical remission, ibrutinib is not intended to cure CLL. There are some on ibrutinib who have reached uMRD, which isn’t recognised as a cure to date, but the closest we can come to it right now. I hope this answers your question?
Is doesn't really fit with PT's idea as subjects either have had 6 years of V+I on FLAIR or are on Ibrutinib as 2nd or nth line for at least 3 years with good response - clinical remission (CR). Also the minimum duration after restarting is 12 months with 6 months in CR. PT is proposing a much shorter time. Pulsed therapy without an initial deep clean of short duration combination therapy or longer duration on BTKi won't result in CR. A pulsed therapy would have to start with at least the initial de-bulking that combination therapies give.
To be eligible for randomisation, participants aged at least 18 years with previously treated chronic lymphocytic leukaemia (CLL) will have already been treated in second or subsequent line of therapy with ibrutinib for at least 3 yearsand be in clinical remission, defined as no palpable lymph nodes, no palpable spleen and absolute lymphocyte count (ALC) <5x109/L, for at least the last 12 months.
In order to begin the initial ibrutinib pause in the pausing ibrutinib arm, all criteria below must be met and maintained continuously for preceding 12 months:
• No palpable lymph nodes and
• No palpable spleen, or
• ALC <5x10^9/L
Criteria to resume/ restart ibrutinib in ‘pausing ibrutinib’ arm:
Any one of:
• Palpable lymph nodes (≥2cm), or
• palpable spleen, or
• ALC ≥5 x10^9/L.
Criteria for subsequent ibrutinib pause(s) (second and subsequent pausing treatment breaks):
• Received at least a further 12 months of ibrutinib, and
Thanks Neil I my CLL specialist has told me my arm does not require my CLL to be in progression. There are criteria to restart based on bloods. If I had chosen to go back on W & W on NHS the criteria would be disease progression. I will read the JM954 post on the subject and take up any queries I might have from there. Thank you for the reminder.
Some quick corrections and additional notes;1. The founding admin for this community is HAIRBEAR_UK, but I have been a community admin since April 2013. There's a bug with how badges are displayed.
2. Your presumed error rate during CLL division will be well under the actual figure, because CLL has multiple drivers. This is why those with complex karyotype CLL statistically have faster progression - a shorter time to treatment. It's also in part why CLL accumulates. CLL cells normally undergo apoptosis, but at a slower rate than healthy B cells, having lost some of the apoptosis pathways as well as gaining additional 'stay alive' signalling. Which of these drivers are in play varies with the individual - it's why CLL is such a heterogeneous illness.
3. Adding a third drug - rituximab to fludarabine + Cyclophosphamide, gave us FCR. This was the first treatment proven to extend life expectancy and was the gold standard treatment for CLL for over a decade. About 55% of those with mutated IGHV have indefinitely long remissions with FCR, with some early FCR trial participants now having had 20+ years of remission. Unfortunately longer term observation of AVO shows just a slight additional benefit from adding acalabrutinib. (I was on the AVO arm in my clinical trial).
4.1 An adult has about 5.5 litres of blood, not 15 litres
4.2 However, in trying to assess the total CLL tumour load, you need to include CLL in the bone marrow, upwards of 600 lymph nodes, including the spleen - a specialised lymph node, which can be a very, very large reservoir of CLL cells if significantly enlarged and possibly other organs, commonly the liver. CLL is most actively dividing in these locations; it's in a dormant phase in the blood.
Thanks Neil, I really appreciate the corrections, and the additional info on FCR. I didn't know it had achieved such long remissions. At 20 years, it's essentially a cure. That certainly goes against my misconception that there would always be a reservoir.
Is FCR still being used as the primary treatment option for mutated IGHV? I had thought BTK and BCL2 drugs had replaced it because of lower toxicities.
Also, I certainly have no idea what the right replication rate is, I just used the rate from the paper you had given me. Of course, the paper was for B cells, not CLL B cells. Do you have a suggestion of what a better replication rate would be?
Thanks again for your update and corrections, it's greatly appreciated.
The CLL tumour growth rate is the difference between the replication rate and apoptosis rate. Both vary widely, which is why some of us never need treatment and some unfortunately need treatment soon after diagnosis.
FCR is still commonly used in most countries for first line therapy for those under the age of 65, often irrespective of IGHV mutation status, unfortunately. BR is commonly used for those older than 65. FCR is still sometimes recommended by CLL specialists in the USA for those who stand a good chance at being effectively cured, but does come with an increased risk of developing MDS or AML.
There may still be a reservoir in those 'cured' with FCR; there's certainly a reservoir, sometimes quite significant, in those who have been fortunate to undergo a spontaneous remission (about 2% of those with mutated IGHV and very few with unmutated IGHV). Some people can grow quite CLL high tumour loads, which can then stabilise or even slightly reverse. The incidence of the precursor of CLL, Monoclonal B cell Lymphocytosis (MBL) becomes increasingly common in the general population with age. Those with low count MBL rarely progress to CLL and those with high count MBL progress at the rate of about 2% per year.
The total mass, number, and distribution of immune cells in the human body
Proc Natl Acad Sci U S A. 2023 Oct 31; 120(44): e2308511120.
They revised previous estimates for almost everything in the immune system. The supplements have graphs and spreadsheets.
The paper focus on a typical adult male, but comments on differences of age, size, and sex and even other species occasionally.
Of course CLL distorts the counts in major ways. But we should keep in mind that most of our lymphocytes and CLL cells are NOT in the peripheral blood, but in the spleen and lymph nodes. In SLL, the preponderence is extreme. I think the estimates of the volume of blood
The authors have another paper about cellular turnover, but it's paywalled. I'll try to email them to get a copy:
I have heard back from the author and head of the lab that produced the total mass, number, and distribution paper. He very kindly sent me the cellular turnover paper plus 2 more! I will share if you PM me.
He also has a website with a draft of a book, Cell Biology By the Numbers:
An associate web site has a searchable database where you can, say, enter lymphocyte, and see many references (sometimes conflicting) to papers for various aspects.
Thanks again for the update. Everywhere you look, trade-offs, which is at the crux of my original post on pulsed therapy,
I want to just clarify the replication rate statistic. While you, of course, are absolutely right on the tumor growth being a function of both the replication and apoptosis rates (the latter of which seems to be the biggest problem in CLL cells), for my argument on resistance from mutation, only the replication rate is relevant.
Mutations are only (or at least overwhelmingly likely) to happen on replication, not after. So since I'm only measuring the rate that a cell can generate a resistant mutation, not the actual overall growth rate. So, I submit it's only the replication rate that should be considered.
While it's only the replication rate which is relevant to the rate at which mutations can occur, that can change over time as additional drivers accumulate from losses in functional apoptosis pathways, or increases in self generated 'stay alive' triggering. As I replied previously "Your presumed error rate during CLL division will be well under the actual figure, because CLL has multiple drivers."
I think you aren't taking into account part of the heterogenous nature of CLL involves mechanisms other than replication and apoptosis. It's not quite that simple. The tumor microenvironment itself gets adjusted as cells cycle from active to quiescent, even before they replicate & any new mutations may arise. There are a number of factors. It used to be believed that CLL was simply "accumulation from decreased apoptosis" but recent research is indicating it's not that simple.
hard to say. I’m p53 mutated and my team opted to leave me on Venclexta indefinitely to avoid giving the clones too much leeway to rapidly explode. Even when I relapsed from Ibrutinib after 6 years, it was a slow controlled relapse that allowed for an uneventful transition to Venclexta. The same logic could apply to switching to CAR T. A lot can happen in 3 month intervals with a pulse therapy approach making CAR less likely to succeed. I doubt I’ll ever get to uMRD so I see these therapies as a more comfortable W&W. Your idea is probably worth exploring the idea further in a trial setting at some point
Belgium but I’m American and receive my medication through American channels. I’m on year 5 on Venclexta. I assume at some point I will relapse, but hard to say when. My ALC was higher than normal a few weeks ago so I thought it was happening then my next CBC it started trending lower again
U r VERY fortunate to have access to Venclexta for 5 years!It only costs my husband $7.70(Aus) monthly …assume if he wanted it beyond 24 months it would cost($7998 ..listed on bottle) which is not a viable option.
Venclexta has been a fantastic option for him as it’s keeping both his cll and multiple myeloma in check.
Yes, it is very expensive. My benefits letter says $9600/month. Was $7500 when I started. I think it’s about 5000€ in Europe. I get it from the Veterans Administration so it doesn’t cost me anything
I think that you are onto something. Somewhere on this site I have even read that something similar is being tested and considered now. Maybe not V alone but the combination of V and I. Like treat for 3 months at a time and then see how it goes. What good is a continuous treatment for those who cannot afford it? Maybe a 3 month treatment every year or two could be more affordable and have the same result? Thus reaching more patients? I hope that these questions will be answered soon enough.
I also recall that, LeoPa. I thought I saved that post but can’t seem to find where ANY of my saved posts are at the moment. Who stole my saved posts? 😎
The gist was what Pulsed brought up - some doctor writing about exploring treating CLL more like diabetes - not going for a “cure” (uMRD), but more just as the chronic condition it is with less emphasis on uMRD? More treatment vacations, if you will. Perhaps I’m misremembering. But in practice here in the U.S. it seems this is being addressed - you’re given a choice of going for uMRD with one year treatment, or going on a pill indefinitely. If you choose the latter, you can try stopping and see what happens.
So is a third option now being discussed/investigated, the plan at the outset being to just do a pill(s) or whatever for a while and stop when bloods and symptoms reach normal levels and then go back to M&M (Monitor & Move on)?
I might be regurgitating some previous replies as I didn’t get through all the long ones, but don’t the one year uMRD/remission driven treatments generally create worse neutropenia? Or is it generally just as bad as with single pills?
I would say the intense combos have the *potential* for increased neutropenia and affecting other cell lines. Look at me, even on intensely marrow suppressive alemtuzumab my neutrophils never got so low they had me on a G-CSF. And I didn't get infections until after, when neuts were "normal" but my T-cells were likely still depleted. Yet I had a single "dip" during induction on venetoclax, which isn't considered as "marrow suppressing" as alemtuzumab.
IMO the problem is CLL's heterogenicity, as well as patient specific factors. Someone 45 going through the same treatment as someone 85 will have at least some differences due to age, let alone other diseases or their CLL markers.
There is distinct difference in heterogenous nature of CLL.
Mutated CLL is far more homogenous. One third are del(13q) and no other genetic markers. 47.2% are del(13q) or have no other del/mut at all. 64% are in just 6 groups, with little complexity.
While the top third of unmutated CLL are spread fairly evenly over 7 groups. Three of those groups (11.5%) having NOTCH1 which is implicated in RS transformations.
This difference could be fundamental to m-CLL being "easy to treat".
Nice observation Skyshark. You're finding a treasure trove in the supplemental data. I wonder why they left 17p/TP53 off this chart, figured that wold be one of the most relevant pieces of information.
TP53 and del(17p) comes with lots of other markers, there is just one pair that are alike, all the rest are n=1. Out of 421, 170 are unique. I'm not even on this chart of 421, none of them match me.
Like me, originally mutated complex karyotype with TP53 mutation and del 17p. Now only TP53/del17p and del13q. Earlier treatment apparently selected for this remaining clone. Perhaps my 13q (plus being mutated) is strongly contributing to favorable outcome. I haven't been tested yet for NOTCH or newer markers, I don't know where I might be on that chart. I also don't know the nature of my TP53 mutation.
"Perhaps my 13q (plus being mutated) is strongly contributing to favorable outcome."
Yes, I've definitely seen that reported. Unlike the TP53, where we know it codes for the p53 protein which aids in tumor suppression, I am not sure how the 13q ties into having favorable outcomes.
"So is a third option now being discussed/investigated, the plan at the outset being to just do a pill(s) or whatever for a while and stop when bloods and symptoms reach normal levels and then go back to M&M (Monitor & Move on)?"
Yes, Chemtrails-USA, that is exactly my thought. When you wrote, "now being discussed/investigated" do you know of anyone actually do this, or just referring to this tread?
If someone was actually doing this, I'd love to find out more. It's been reported in this threat that at the end of the FLAIR trial, patients were given a choice of continuing ibrutinib continuously, intermittently, or not at all. That was the only reference I could find to a pulsed strategy, but even then, that was at completion of the trial.
I do know that my CLL Specialist, who is heavily involved in lymphoid malignancy research, just served a term on the Ethics Committee of ASCO, and currently is serving on the Committee on Practice of the American Society of Hematology. Our discussions have been more along the line of reaching uMRD (I didn't specifically ask if uMRD4 or uMRD6 would be the criteria) for X amount of time, going off the drug, and if a remission/disease and/or symptom quiescence lasted X amount of time, simply retreating a relatively short time period could be considered.
Taking into account I have both a TP53 mutation as well as some 17p deletion, and haven't had severe cytopenias or other side effects, he originally told me, for me personally, that a 2 year remission window would be needed for repeat retreatment. But something has changed; at our last meeting, he told me repeat venetoclax is OK if I want to do it. That's only 1 year remission. IDK why he changed from what was said previously. I wonder if the discussions around a "pulsed therapy" concept among practitioners has anything to do with it.
I don’t think any practitioners are talking about pulsed therapy despite the group that studied this for prostrate cancer.
With mTP53, resistance to me seems more probable than without.
So I’m back to my question, why go on continuous Venetoclax rather than just taking it when you hit some metric, ALC>10e9/L or have palpable lymphocytes, for example, and forget about uMRD.
Since there’s no study, we don’t know. But why not ask your specialist, and bring the SciAm article?
When I originally posted this idea, I knew it was from left field, but not any more. This incredible community has really helped give some credence to it.
After 12 cycles CLL14 V+O trial has shown that failing to reach uMRD4 is a sticky wicket. OK CLL14 was for patients median age 71, having CIRS score >=6 and unfit for FCR/BR.
It could be argued that repeated short duration therapies are pulsed but how short can you go and not be joining the 50% dead in 6 years camp?
There is a current trial of V+O that can discontinue at the end of 9 cycles based on being uMRD-5. It also extends treatment to 24 cycles for those that are dMRD (detectable disease).
CLL14 by end of cycle 6, 72% were uMRD-4, 61% uMRD-5. By cycle 12 that number had hardly changed but uMRD6 had increased from 34% to 50%. Dr Brian Koffman's (n=1) observation is that a factor of 10 reduction gives nearly an extra year before next treatment.
As far as anyone could tell from a blood test I was in remission by day 5 of treatment after the first dose of Obinutuzumab. ACL had gone from 105x10^9 to 2.24 by day 5. Other people have been told they ARE in remission by doctors at this point.
Still had massive lymph nodes, only the peripheral blood had been cleared. The pleasingly low ALC continued for the next 2 doses day 8 and 16. The first week of 20mg Venetoclax starting on day 21. Sometime between Monday D27C1 and Wednesday D1C2 my WBC jumped from 6.5 (with ALC 1.37) to 13.78, my neuts have been quite stable so it was all lymphs. I don't have ALC as these were TLS blood tests for chemistry but there wasn't an immediate fall on Thursday or Friday after 4th dose of Obin on Wednesday and 50mg Ven. By the following Monday WBC was 7.3 and ALC 1.6. It would be another 2 weeks before the lymph nodes I could feel in my neck had gone but I had never been able to detect the biggest clump of nodes in my mesentery 21x14cm. That clump wasn't confirmed to have gone until a CT scan at cycle 7, when I had a unconfirmed complete response. Unconfirmed as there wasn't a bone marrow test until a month after end of cycle 12.
Could I have stopped at cycle 7,8,9? Possibly with invasive BM testing and a uMRD4 result. But I had bulky lymph nodes with a hazard ratio of 1.916 on 12 cycles of treatment. My unknown IgHV but Atypical, ATM del and SF3B1 mut all point IgHV unmutated with a hazard ratio of 2.258 (12 cycles). Then there's the apparent exhaustion of Obin and bounce in WBC at start of cycle 2 as lymphs left the nodes. Also slightly elevated above normal Kappa free light chains that unlike the dramatic drop in Lambda were untouched by Obin and only reduced very slowly on Ven (possible bi-clonal, CD20 neg?). Being in the 2% that are still high risk TLS at day 22 after first 3 doses of Obin. (Not to mention the lack of MRD testing when I specifically asked about it and I now know other NHS hospitals do test.) I'd prefer to do 18 cycles every 5 years (with luck!) than 6 cycles every year.
I've been curious about improvement of uMRD status with longer duration of Ven after completing the V + O cycles.
My oncologist showed me some data from R/R patients on V + R that showed not much better MRD status was achieved after the first 9-12 months compared to those at 2 years total on Ven.
However, in the same Murano study group, stopping treatment early led to shorter PFS where as dose reduction did not. I had a hard time following the logic of either of these 2 studies.
Do you have the citation for your comment
CLL14 by end of cycle 6, 72% were uMRD-4, 61% uMRD-5. By cycle 12 that number had hardly changed but uMRD6 had increased from 34% to 50%. Dr Brian Koffman's (n=1) observation is that a factor of 10 reduction gives nearly an extra year before next treatment.
Just hate to stick it out another year on Ven if my MRD status is not going to improve much and I end on some sort of treatment for the same amount of time now v. later.
I think it makes complete sense that stopping early leads to shorter PFS, but I don't think that is the relevant question. The more relevant question is what happens when the disease does come back, and while we hear about some very long remissions, that is far from the majority. When the disease returns, does it still respond to the known drugs? This is the essence of my post. Is it a mistake to drive the disease down to uMRD6 or better, and thereby, possibly create a reservoir of CLL selected for drug resistance? Or is it better to get out early leaving a much higher reservoir around, but that reservoir having been far less selected for resistance. As long as you have a heterogenous population, when selective pressures are removed, the different strains naturally compete with each other so the line selected against the drug will no longer be dominant.
As PulsedTherapy comments very few that aren't at uMRD4 by cycle 7 ever get to uMRD5. While those that have reached uMRD4 increase the depth of uMRD, mainly in cycle 9 to 12. All the increase at first 3 month follow up (FU3) can be attributed to the increased number that moved out of "missing". While as PulsedTherapy rightly observes the MRD suffers quite rapid conversion uMDR6>uMRD5>uMDR4>about 2 years>dMRD>depends on progression rate>Next treatment.
CLL14 6-years as previous link. CAPTIVATE FD - 4 years (supplementary results). Offset is due to V+I being 15 cycles, 14 months and CLL14 reports for time from end of treatment.
I overlaid the PFS KM charts for MRD from these two trials.
CLL14 - 23/212 = 10.8% dMRD.
CAPTIVATE FD - 57/159 = 35.8% dMRD.
As was seen on FLAIR V+I trial mutated IgHV are slower to reach uMRD. Also V+I is slower overall compared to V+O. This results in a greater number not reaching uMRD on 15 cycle V+I that do on 12 cycles V+O.
At 34 months after end of treatment the number with dMRD that had progressed on CLL14 was 14 (6.6% overall) and 20 (12.6% overall) on CAPTIVATE FD. Although the Kaplan Meier line for CAPTIVATE FD dMRD appears better it's outcome is actually worse in absolute terms. It also has to borne in mind that CLL14 patients were median age 71 with CIRS >=6 and unfit for FCR/BR while CAPTIVATE FD median age was 60.
BUT - there's always one.
The slower responding mutated IgHV on CAPTIVATE FD are a lower proportion of those that have been re-treated with Ibrutinib. Four (23.5%) out the 17 that are listed (19 actually on re-treatment), one of those has del(17p) and two are complex karyotype. Compared with 44% being m-IgHV. The 4 are 5.7% of m-IgHV, while 13.6% of u-IgHV are on re-treatment. Although they have a propensity to not reach uMRD on fixed duration treatment, this shows they don't need to reach uMRD.
So I think my question becomes one of time to next treatment with V + O in the R/R setting after stopping treatment as a function of stopping at say 16 months as opposed to the full 24 months.
Nice chart Skyshark. In fact, that link to the CLL14 study had a wealth of well presented graphs. Here's my takeaways:
1) TP53 and uIGHV clearly have shorter PFS. I am not sure why uIGHV would, but certainly it makes sense del17p/mTP53 would (tumor suppressing gene). Those CLL cells are much more able to mutate under selective pressures.
2) no matter what the level of MRD, almost universally there will be a reoccurence.
3) if you cannot achieve uMRD, which is highly correlated with del17p/mTP53, the overall survival is much lower (not from this chart, but the overall survival according to MRD status in the same paper). So follow up therapies are not effective.
4) back to my original post, if it is in fact additional mutations under selective pressure are causing
a) not be able to achieve uMRD4
b) the reason follow up therapies become ineffective
Then this highlights my point that therapies should be given in the lowest amounts for the shortest durations that achieve, not uMRD, but just manage the chronic symptoms, in this way to place the least amount of selective pressures on the CLL cells, and especially in del17p/mTP53 because they have the highest risk of creating mutations.
I am not an evolutionary biologist, so take my musings with a handful of salt. But in your example, it isn’t really the percentage of del17 cells that matter, it is the absolute number - no? If you eliminate 80% vs 99% of non-del 17 cells, I don’t see how this has an effect on mutation rate of the del 17 pool. Is your thought that del 17 cells are somehow competing with non-del 17 CLL cells?
Hi BobbyFour, well, neither am I, so keep the salt out.
I don't think there is any difference in the mutation rate of del17/mTP53 cells vs other CLL cells with other genetic configurations, but the TP53 is a tumor suppressing gene. So when random mutations happen, the TP53 can signal the cell into apoptosis, so it never gets a foothold. If a mutation happens in a mTP53 cell, the natural process for killing the cell aren't there, so it is far more likely to gain a foothold.
But even if there's a mutation, and a new clonal line begins, it is only going to take over if there is some selective pressure that increases the new clonal lines fitness. Otherwise, it's just one mutation among many. So the problem happens when a mutation occurs that confers resistance to one of the CLL drugs like venetoclax, for example. Here it may develope a mutation in the BCL-2 protein that causes the venetoclax to lose effectiveness.
If you stay on long term venetoclax when your MRD is has stopped decreasing, it would seem that the CLL cells have developed a resistance. And my staying in the drug, you are guaranteeing that the only cells left will be venetoclax resistant.
If you are on the venetoclax (and I'm just using that as an example here) for a short term, and you do develop a resistant line, but have gotten off the drug, you also remove the selective pressures. So venetoclax resistance mutation no longer has a selective advantage, it's just like any other CLL cell. And all the CLL cells compete metabolically and physically in the body. So over time, you have a mixed population, not a resistant population.
Then, when you need to retreat, the original drug should still be effective. What I see in the literature is that these drugs are very effective in treatment naive patients and then almost universally lose their effectiveness. So I'm more worried about the next treatment, not the current one. And this novel idea of not attempting long course therapy to bring you to uMRD is a trade off to maximize the chance you don't develop a resistant line.
I could be wrong, but I am reading that “p53 contributes to genome stability in multiple ways (e.g., by inducing apoptosis, cell-cycle arrest, and DNA repair)”. So, at least in the case of those particular cells, I think they are more prone to mutate than other CLL cells? So at least in that case, wouldn’t fewer of those cells mean less opportunities for further mutations? I think, and again I might be totally wrong, that allowing the growth of a tp53 dominant population is a particular problem (vs other mutations) as that specific mutation allows its progeny to more quickly evolve around future treatments.
Regarding the general principle, there is an analogue in antibiotics where stopping treatment early actually increases the opportunity for resistance. I would think you want the treatment to kill as many cells as fast as possible to lessen the statistical chance for an escape mutation. It feels counterintuitive to me that leaving more cancer cells alive is beneficial long term. But again, I am not an evolutionary biologist 😀 My son has a friend who is an evolutionary biologist, I will ask him what he thinks - this hurts my head, lol.
1) Yes, TP53 is more prone to mutate and yes, you want less of them, absolutely. This does make the case for early treatment. Instead of wait and see: treat, wait, and see. But that's another story.
2) And while yes, while less is better, you are still faced with a trade-off because it's not so easy to just make less of them.
First, remember, CLL isn't curable, so you can never get to zero, there's always a reservoir. And also, remember we measure B cells on the order of 5e9/L and with 5 liters of blood and maybe another 5 liters tied up in lymph and BM (I don't know if that is right, but wanted to account for the lymph and BM in some way) you have on the order of 50E9 cells in the body or 50 billion. So even if you can get an uMRD6 (1 in a million), you still have a reservoir on the order of 50,000.
So here's the tradeoff. If you treat long term you may very well end up with a tiny population of 10,000, but what if they are all drug resistant cells, and when it inevitably comes back, you have no bullets in the arsenal. Or, treat short term, and have a reservoir of a 5 million, but a very heterogeneous population. So as it replicates and comes back, only a fraction are resistant. And you can treat again.
In-between treatments, the resistant population has no competitive advantage (the drug is removed), and is not going to overcome the other strains. But if you select heavily for the resistant strain, then when they replicate, you will largely have the resistant strain (you only had the resistant strain to start).
Everything, everywhere in life is tradeoffs (Thomas Sowell).
As you said, you can pour salt on my ideas, and rightfully so, I'm just presenting it here to what I've found is an extremely intelligent and knowledgeable community for thoughtful dialogue and criticism.
flyfish21 posted a SciAm article that essentially parallels this paradigm shift in treatment. Respect the microenvironment and cancer's evolutionary course, and instead of treating to uMRD, treat it chronically to avoid resistance and adverse reactions.
I look forward to hearing what a real evolutionary biologist has to say.
Well, bad news - the evolutionary biologists are both microbe focused, and so they said we really need a cancer biologist as there are different factors at play. But the good news is they didn’t think we are complete morons (😂), as they are guessing it is the balance between reducing the pressure to mutate (your point) and allowing too many cells the opportunity to mutate (my point). They also noted the micro environment makes things very different than ‘normal’ evolution of microbes. Sorry I don’t have a good answer. But it is a fascinating question!
There may be a new treatment available providing this option in the future. But I don't think this approach is desirable with existing treatment options.
For one, CLL is slow growing, so initial 'improved' results are only superficial and aren't an accurate account of how the disease is likely to progress if treatment is discontinued. It may come back with a vengeance or damage other organs once released into the blood stream. Doctors would have a very difficult time predicting how it would behave if treatment is suddenly halted.
Second, the average age of diagnosis should be considered. Do people really want to be back in the hospital every year for treatment, especially if they also possibly deal with heart and lung issues in between their CLL treatments? Their immune system is suppressed everytime they have treatment, making you more susceptible to infections that you are ilequipt to fight off. You're also more susceptible to secondary cancers. So there is the potential of being diagnosed with another cancer or illness every year you go for a check up.
Third issue is the cost. Not just the financial cost of treatment, but the cost of potentially being out of work annually and needing help from loved ones, which some people aren't able to rely on. Also, there is the cost of the sustained trauma from undergoing treatment year after year. Dealing with incompetent medical staff, waiting anxiously for test results, needing to have every cough and pimple checked for fear of the worst... The emotional and psychological toll is as detrimental as the physiological burden, if not more so.
Finally, from what I understand, reliable treatment options have only recently become available and are not available to all. Our bodies are extremely sophisticated and adaptable. I'd be concerned that this approach may work for a year or two or even five, but your body would quickly become resistant to the treatment and your options would then be very limited within a shorter time frame. Whereas completing a full course of treatment could give you a longer remission with fewer complications in the long term.
I can completely understand why you are suggesting this approach, but I don't think our healthcare systems are prepared to accommodate it. I think becoming disease free and managing the residual effects of treatment is a better option than repeatedly antagonising the disease and waiting to see how it reacts.
It is always up to the patient whether they want to discontinue treatment. But asking people to volunteer to have this method trialed on them, given the wider implications on their wellbeing, would be medically and socially irresponsible.
Having cared for my husband and seeing him left in worse condition than before he was given any 'medicine', I can concede that our current options leave a lot to be desired. But I couldn't imagine going through this on an annual basis, knowing in the interim that his CLL could be getting up to all sorts of mischief between appointments.
This approach is potentially desirable for patients who's disease isn't responding to treatment and so their only option is to have it managed rather than treated. But if remission is an option, it should probably be aimed for rather than giving a volatile disease the opportunity to develop a defense against its eradication.
Yes, very interesting as health care is now striving for individualized patients' treatments, unfortunately we maybe light years away from that solution.
Thanks so much for sharing your thoughts on this, really, what a great post. All your concerns seem very valid, there are nothing but trade offs and its difficult to weigh each with not only incomplete information but the heterogeneity of the disease.
Two things I'd like to explore:
"Their immune system is suppressed everytime they have treatment, making you more susceptible to infections that you are ilequipt to fight off."
This highlights my question on trade-offs. Let's take two scenarios for example, and yes, we know these are just two simple examples and CLL is far more complicated, but just for illustration:
scenario 1
You go on VO for 12 cycles and achieve uMRD and gives you remission for 5 years.
For that year of therapy, you will probably suffered neutropenia and possible have created a VO resistance reservoir that may not be responsive at year 5.
scenario 2
You go on VO for 1 month, reduce ALC count to just under 1e9/L but have to repeat this every year for 5 years.
Certainly, the chance of neutropenia and its complications should be lower, only 5 months of being immunocompromised vs 12, and I'm suggesting less chance of VO resistance because there has been less replication cycle time to develop a resistant mutation under shorter duration selective pressures.
So I see reasonable tradeoffs that make a trial worth exploring. Certainly, on the pulsed therapy, you can monitor closely, and if it isn't working, you can switch to a more standard approach.
The other very thought provoking comment is " left in worse condition than before he was given any 'medicine'," I have certainly been thinking about this independent of pulsed therapy. These are powerful drugs, with profound effects on the CLL cells, their micro environments, and release from their micro environments. I've read, for instance, with Ibrutinib, peripheral blood counts increase initially, owing to a migration from the BM. This makes me wonder if treatment naïve (TN) patients, are better served by waiting as long as possible, or better treating as early as possible. More trade offs. If you treat early, there is less disease, so a lower chance of TLS, and less heterogeneity in the disease itself (as it hasn't had time to create as many mutations). But on the other hand, the treatment itself can compromise your system and affect the progression of the disease in unintended and unseen ways. And of course, staying TN leaves you ready for new trials as the landscape and advancements for CLL keep coming.
Thanks so much for your comments and sharing your thoughts.
First of all, I think your reasoning is very sound in just about all aspects. Thank you for taking care of your husband, furthermore, as you used past tense I'm guessing he may have passed, if so my condolences.
To then, in a theoretical discussion try to parse your complete care journey during your husband's illness isn't anyone's privilege but your own - you lived it from beginning to end.
I do make comment on this one phrase and please feel free to clarify or correct me, "It is always up to the patient whether they want to discontinue treatment. But asking people to volunteer to have this method trialed on them, given the wider implications on their wellbeing, would be medically and socially irresponsible". (my emphasis)
It is only during a trial that it seems that it would be responsible and ethical, certainly not during a course of standard therapy would any professional try to suggest the added implications. Like I said, we may be saying the same thing differently, I am infamous for protracted misunderstandings on the Gordian level, if so, pity this fool.
I use past tense because my husband is in remission from both CLL and CNS lymphoma. He is dealing with a variety of residual issues, but all more manageable than cancer.
I say it would be irresponsible to propose a trial of 'pulsed' treatment because of the known impact of treatment on people's lifestyles. I understand that V+O is better tolerated by many, but that wasn't my husband's case at all. And when I think of the difficulties other patients had arranging transport, benefits, time off work and accessing support from family and acquaintances, I just don't think it would be ethical to ask patients, particularly with comorbidities, living alone and experiencing varying degrees of discomfort, to subject themselves to this experience year after year.
Treatment was gruelling and I lost count of the number of times the only option my husband was given was between life threathening treatment or certain death. The only perceived benefit to consenting to treatment was the potential for it to give my husband several more years of IV-untethered freedom outside of hospital, even if those years were limited or restricted by immunocompromised considerations.
I admit that I place a lot of value on the mental aspect of healthcare. The psychological toll was by far the most violent aspect of my husband's treatment and I'm not sure he will ever recover psychologically, even if his physical health improves. And I unfortunately met many patients and caregivers who were left with similarly devastating psychological scars, despite having had better prognostic outlooks than my husband and successfully achieving remission.
Even if a revolutionary new treatment option could mitigate the risk of disease mutation or progression between courses, the healthcare industry would have to entirely revise its policies and practices before I would vote in favour of voluntarily taking my husband to the hospital more than I currently need to.
We really shouldn't overlook the importance of holistic care when considering treatment options. I'm still haunted by the patients I met but suddenly disappeared because there were no medical professionals to answer their calls for help in the night.
I suppose I agree that theoretically, the healthcare industry could be doing way more for us, but realistically they are too overburdened and disillusioned to deliver the intricate monitoring that a pulsed treatment plan would require.
Thanks for sharing Blue-bird, no doubt it has been rough, and I can't challenge at all your experiences with the "system." But FlyFish21 just posted an extremely interesting article from SciAm that I hadn't known about, that offers considerable evidence and arguments for a pulsed therapy. It's worth reading.
"In a clinical trial with prostate cancer patients, one of us (Gatenby) tried an alternative to the scorched-earth approach, applying only enough chemo to keep the tumor tiny without killing it entirely. The goal was to maintain a small population of vulnerable chemosensitive cells. That population did well enough to prevent cells with an unwanted new trait—chemoresistance—from taking over."
I'm first glad to hear that I was wrong about your husbands current life status! 🙂
Second, I honor your perspective, you sadly have earned the right to see and to say how you see it.
I guess I assumed you miss spoke when you said it shouldn't be an approach in a trial. After all, how did we get any of the modern medicines, therapies, and modalities but through well staged trials.
Regardless, your account is of personal value to me, everyone on this journey does need to hear the dark side of what treatment can be. Whatever treatment course they're considering, one has to do some real soul-searching and not just listen to the sales pitch.
There is a place for optimism, but at some point, I think hope needs to take a time out and oncologists need to be brutally honest.
Haha! I do think a pulsed treatment option seems logical since CLL is a chronic illness. Most other chronic illnesses are managed this way, after all. And if a person with CLL is in generally good health, it would make sense that they only need 'minor adjustments' when their numbers start to progress in the wrong direction.
My husband worked as a secondary school science teacher before his diagnosis, whereas I never really understood much about cells and atoms and whatnot. But what I have learned since his diagnosis, is that CLL is far more complex than even the doctors understand. And unfortunately, there seem to be more illnesses than there are research teams, so it may be a while before a treatment option is available to manage CLL on a less invasive basis.
I agree that this approach is desirable, but from what I gather, our immune systems are very good at adapting, for better or worse. Every patient's biology is also so different, not just the genetic presentation of the disease itself, but other commorbidities and acquired conditions would likely make stopping treatment prematurely a very risky gamble.
Although, as I think more about this, its possible that CLL may behave similarly to HIV and AIDS? There is CLL and Richter's transformation. AIDS was initially a death sentence, but now many people don't progress beyond having HIV and indeed, their HIV reaches a sort of remission after prolonged treatment, but this is probably more resemblant of V+O treatment than a pulsed therapy. Perhaps instead of a pulsed treatment, what we need is simply a less aggressive treatment option with fewer side effects?
If decreasing the risk of TLS or mutation is the aim, rather than 6 months of obinituzumab, maybe they could change the protocol to quarterly obinituzumab infusions with a half dose (2 rather than 4 pills) of Venetoclax taken over 4 years? This way remission remains a possibility, but the obinituzumab infusions are not as disruptive to the patients daily routines and not as much of a burden on their immune system.
Someone with more medical knowledge than myself would have to workshop this concept for me, but I imagine that apart from the desire to keep the financial costs on the hospitals lower, the reason the treatment is administered over 2 years rather than 4 or more is to increase the chances of achieving remission before the immune system figures out how to circumvent the V+O's effects on the disease.
Very interesting concept but as there are so many unknown variable's because of each person's health issues (which also add pressure to mutation) I would say in a perfect CLL world this would work! I think the current research in the CLL drug labs is so fluid that they truly are throwing all kinds of new time treatments at it. My new CLL doc at MDA said they they are rethinking the concept of treating with 1 or 2 drugs over a life time on a daily basis and treating with 3 different drugs for a big knock out and possible cure. I have no idea what this combo is but I think it would have to be only available to treatment naive patients because they have a clean slate. I think they have so many choices now and each one has it own side effects, so on a large scale of aging boomers you have to wonder how many would even qualify for this hard and fast treatment? I will find out in Aug, but because of a few of my health issues, I think I will be high risks. I will say it is a better position to be in now vs a decade ago when everyone was treated with the same group of drugs. I do like your idea though, so thanks for sharing!
i read about a study that started a year ago where they did just that.
Ven + Acal for 3 months periodically
I wish I could recall the citation
The premise was that these intermittent treatments would improve immune function
There are a lot of theories for and against this approach
I don’t know the answer.
Right now I’m at uMRD 4 in blood but have 4/10,000 CLL cells in marrow. Multiple data plots show that return of disease would be around 5-6 years as opposed to 2-3 years if i continue treatment to uMRD5 or 6.
So for me the question is will continued treatment now lead to longer PFS or buy more time off treatment than on.
"i read about a study that started a year ago where they did just that.
Ven + Acal for 3 months periodically"
Wow, I will have to dig around for that. That is exactly what I've been proposing, admittedly rather naively and without data.
Congratulations on uMRD4. And you propose another excellent question: is it worth prolonging therapy to continue to uMRD6 or stop now? I wish I could offer any insight, but do acknowledge that this is a very very tough decision -- I'm not sure anyone knows what the right call is.
It's a frustrating difficult call. If you stay on the drug and MRD still declines, at least you are seeing some benefit, and that benefit is weighed against the adverse consequences of the drug itself, from neutropenia to CLL resistance.
On the other hand, if MRD isn't declining, you would think then, why stay on the drug, but maybe the drug is keeping the MRD from increasing, and when you remove it, the MRD will accelerate.
If it does, I suppose, you can always go back on, but then you are left with the question, did the on-off-on strategy cause some resistance?
Very difficult evaluating these trade-offs, I wish you the best.
Here's a trial (in Denmark) that does three cycles of A+V but it's not quite the intermittent therapy you're asking about. skipro
Acalabrutinib and Venetoclax Treatment of Newly Diagnosed Patients With CLL at High Risk of Infection or Early Treatment
OBJECTIVE AND HYPOTHESIS Phase 2, randomized study of short-term, combined venetoclax and acalabrutinib treatment of newly diagnosed patients with CLL. For patients identified by CLL-TIM (the Machine Learning predictive algorithm, Treatment Infection Model) at high risk of infection and/or early CLL treatment, it is tested whether grade 3-Infection-free, treatment-free survival can be improved by three months of venetoclax+acalabrutinib treatment. Changes in immune dysfunction are measured by an extensive translational program for correlation with changes in infection.
Awesome, that is an absolutely great study, thank you. While it's not a pulsed strategy per se, it is a short term treatment, but it addresses another very important issue: when should a TN patient begin treatment and how?
I have been thinking about this too in conjunction with the pulsed strategy. Certainly hitting the CLL earlier has the benefits of reduced TLS, it also should have the ability to work in cells CLL cells that are not lower heterogeneity, as they haven't had a chance to undergo many replications yet, and at 3 months, it reduces the chance of resistance and neutropenia.
The limit on high risk patients seems to be an ethical and practical choice, because why begin a treatment on people whose genetic prognosticators show a good chance of a decade of indolent behavior.
I do want to point out a concern I have of the treatment strategy"
acalabrutinib on day one
venetoclax ramp up on day 1
If acalabrutinib is like ibrutinib, I'd expect CLL cells released from the BM into the PB. I'd rather they'd be more venetoclax in the blood when the aclabrutinib is initiated. I'd suggest starting the acalabrutinib in week 2 or 3 of the venetoclax ramp up so the venetoclax is at blood levels high enough to reduce the increased CLL cell population caused by the venetoclax. Just a thought.
Thanks skyshark, they certainly know something. Do you know their reasoning? Could it be they are worried about TLS with venetoclax, so they first go with BTK to lower the load?
It's very much a case of worry about TLS and costs of "high risk TLS" ramp up as an inpatient.
For V+O the initial 3 doses of Obinutuzumab before starting Venetoclax results in a ten fold reduction of "high risk TLS" patients, from 20% to 2%. They re-stage patients at end of week of 3 by bloods and CT scan to check lymph nodes. This can save 2 inpatient stays of 3 days / 2 nights for first and second doses of 20mg and 50mg Venetoclax but wont avoid the 4 day / 3 night inpatient stay for first dose of Obinutuzumab.
The 3 cycles of initial Ibrutinib have about the same results. 21% at high risk TLS reduced to 1%, 18% high and medium risk as inpatients reduced from 40%.
That is great information Skyshark, makes perfect sense, and explains exactly why the protocols are overwhelmingly the way they are. Makes me wonder why the even give venetoclax alone. Although, I suppose that depends on your risk group. Thanks so much for clarifying, I really appreciate it.
This is very interesting. My husband was told he had 100% disease infiltration in his bone marrow but his CLL wasn't detectable/diagnosable in his blood. Potentially because his counts were close to zero across the board when he was diagnosed.
They started him on V+O and his condition improved, but the improvement appeared to be due to the steroids rather than the immunotherapy.
He was never staged or restaged at week 3, presumably because he had neurological symptoms and they suspected he had Richter's, which turned out to be CNS lymphoma, also b cell but independent of his CLL.
He had a biopsy in February which showed 100% disease infiltration, had 3 cycles of V+ O, and in August his subsequent biopsy showed zero evidence of CLL. The V+O was discontinued after 3 cycles to start chemo in June.
I have always wondered whether he actually had CLL, because it has not shown on a single blood test ever, though in fairness he was pretty much kept alive by blood transfusions during that first year following his diagnosis. But his biopsies have also all been clear of CLL apart from the very first one.
Is V+O really that effective? I suppose time will tell as his remission is unlikely to last forever?
Maybe skipro is referring to the Majic trial. It starts with 3 months of Aclabrutinib but then adds Venetoclax for about 9 months. At that point tests for MRD6 bone arrow, CT and others.
I find it an interesting idea PT, and one that's generated some informative comment, which is what this site is about - that and mutual support. Thanks for your contribution.
You say If you reduce the CLL count to a very low number, and those CLL cells left, which are likely to have survived by selective mutations, and exist at least on the order of 1000...
In practice treatment would be stopped at a prescribed time or number of treatment cycles following achievement of uMRD, but nobody would know how many cells remained by the end. Judging from the ALC curves you show for I + V, which flatten off after 12 months even on a log scale, I think we're looking at a minimum of hundreds of 1000's of surviving cells. According to my arithmetic, 2 to 5 million CLL cells in peripheral blood is the measurable limit for flow cytometry, 20-50,000 cells for NGS, these values corresponding to uMRD4 and uMRD6 respectively.
Yes, 1000 is somewhat low, because that calculation was just accounting for CLL cells per liter. Here are details of my calculation, please let me know if I still have it wrong. And thanks for the links!
The correct calculation would be something like this:
uMRD6 means less than 1 CLL cell in 1,000,000 normal cells.
In normal blood, you may have 1e9, a billion, lymphocytes per liter.
So, the estimated reservoir at uMRD6 is less than:
(1e9 normal cells / L) * (1E-6 uMRD6) * (5.5L blood/body) (2 doubling the # in the blood to account for the lymph system and BM - just an estimate here)
uMRD6 in peripheral blood means less than 1 CLL cell in 1,000,000 white blood cells; in bone marrow means.. .in 1,000,000 mononuclear cells.
Assuming post treatment WBC to be in the normal range 4 to 10 × 10^9 /L, 5L of peripheral blood contains 2 to 5 x 10^10 white cells. By simple division, the upper limit for dMRD6 is 2 to 5 x 10^4 CLL cells, i.e. 20,000-50,000, and for dMRD4 is 2 to 5 million.
In clinical trials MRD may be measured in both blood and bone marrow; in clinical practice often neither. I doubt that MRD is checked in secondary lymph organs other than for research.
Courtesy of Skyshark I found a graphic in nejm.org/doi/suppl/10.1056/... Figure S2 relevant to this question of residual CLL cells following treatment. The figure relates to the FLAIR trial, and the paper is nejm.org/doi/full/10.1056/N... which you may need to register (free) with NEJM to read.
Note that the uMRD4 line is around 10^6 to 10^7 total body CLL cell numbers.
Very nice Bennevisplace. At least my calculation was in the ballpark. But I don’t want to lose sight of the original reason for my post, which is questioning going for a uMRD at all.
Flyfish21 found an SciAm article speaking directly to this idea as a paradigm shift in treatment. They described it much better than I have:
"In a clinical trial with prostate cancer patients, one of us (Gatenby) tried an alternative to the scorched-earth approach, applying only enough chemo to keep the tumor tiny without killing it entirely. The goal was to maintain a small population of vulnerable chemosensitive cells. That population did well enough to prevent cells with an unwanted new trait—chemoresistance—from taking over."
Exactly, this was one of my rationales behind stopping venetoclax after year 2. I was and still am uMRD4, which up until more sensitive testing was the "gold standard". And now there are studies trying to determine to what extent depth of uMRD4 or uMRD6, how quickly one reaches it, how long one needs to continue treatment if at all, affects quality of life and disease occurrence. So some may say it's unfortunate these questions have yet to be answered. I personally am happy to be around, had my particular variant popped out even 5 years earlier I doubt I would still be here. So this uncertainty isn't super bothersome IMO, the alternate would have been worse.
Hi Skyshark, I think this is the table. It definitely indicates diminishing returns after 6 months. So, for instance, in the >100e9/L group, they kept 27 people (I don't think they stopped the therapy when uMRD was reached in this study, not sure) on the VI from 6 months to 9 months, with no one becoming uMRD who wasn't already uMRD at 6 months. While the ALC may have decreased, even if it didn't go below uMRD, I fear that keeping selective pressures on for this long is in fact creating the very resistance that makes treatment difficult after a some time of PFS.
Rate to reach uMRD4 (assuming it's 10^-4 because this study was from 2019)
ALC is a misleading statistic for effectiveness. It doesn't go deep enough, and shows all lymphocytes, and not just B-cells or CLL cells. Two people with identical ALCs may have a very different mix of CLL, normal B-cells, T-cells, and NK cells. That's why there's MRD testing.
Thanks Seymour. Good point. I’ve seen clonal B cells reported which seems a better indicator, but I am not sure how they determine MRD. I know it’s x cells in y, for example 4 cells in 10,000, but how do they determine that? Is it 4 clonal cells or something else? Thanks.
For Flow Cytometry MRD, they separate the white cells from the rest of the blood, and then use monoclonal antibodies that are attached to different colored fluorescent molecules for each of the target CD's they wish to identify. I believe each individual WBC then goes through the instrument where different colored lasers make the fluorescent molecules glow, and a scatter plot results from the sensors for the lasers. By counting just the scatter plots that show evidence of the combination of CDs that match CLL, they can count individual CLL cells and compare that count with the overall cell count. I don't know the further details that limit the sensitivity to 1 in 10K or 1 in 100K for newer FC MRD. So FC MRD doesn't identify specific, unique clones. It identifies CLL cell characteristic markers.
For ClonoSEQ, they use RNA tags that match the headers of several IGH, IGK, and IGL genes to select the BCR's (B-cell receptors) to count. They sequence the rest of the gene, and use a sensor connected to a computer to tally the quantity of each BCR. The ones that greatly outnumber the rest are identified as dominant clones, and used for the later MRD clone test where they look for those specific clones, plus any new ones that greatly outnumber the rest. Again, I'm not sure of what limits the final sensitivity to 1 in 1M. My own ClonoSEQ found a single dominant clone in 2.8M in my final bone marrow sample, which is less than the FDA-validated 1 in 1M. The test of PB (peripheral blood) found none. Marrow is considered the best source, but is obviously more expensive and logistically difficult. Many results have been compared now over the years between marrow and blood, so there are fairly predictable proportions.
Unlike FC MRD, ClonoSEQ requires a pre-treatment test to identify the dominant clones for later comparison. A nice bonus is that it gives a count of all BCRs, which can indicate B-cell recovery.
FC MRD is cheaper - several hundred to a thousand dollars US, I believe, depending on the lab. ClonoSEQ is about US $2,000. A CBC/Differential ranges from US $50 to a little more than $100, I believe, depending on what deal the lab has with specific insurance companies. As time goes on and technology improves, both will get even cheaper.
Excellent Seymour. Very informative. Certainly way better than simple ALC. Thanks, I really appreciate the info. Also, I found your post on the infusion headache, "A trial and some tribulations." This therapy has really worked out for you now, but must have been scary when it was happening. But I doubt you will ever find obinutuzumab on a Scrabble board.
You have put some thought into your consideration regarding uMrd. This is one of the aspects of my not having an argument but rather a conclusion for my point of view that I exposed in a recent post.
There is enough data across a variety of studies to stimulate multiple valid possibilities, yet the quantity of outcomes is not there to support one over the other.
From a data perspective, an argument can be more of a "if this then this" or "greater/less than plus equal to" measure instead of the weighing of speculation which may over amplify the emotional influence to a measure.
So at this point, it is acceptable to consider how uMrd might be helpful to the individual with their unique treatment goal(s).
I hope your conclusion is helpful to you and others with similar circumstances.
Thanks for you thoughts Smakwater. What you described is what makes decision making so hard, there are not completely conclusive studies, so we are left with trade offs that we have to make on incomplete information. Skipro in this thread is in the middle of doing exactly that.
But I do want to make note that I have no "conclusions" at all. I'm just thinking out loud on some ideas that have come to me while thinking about CLL, and really, am grateful to have found this community that is so knowledgeable, supportive, and willing to share their experiences.
As Smakwater states if they all, "at this point, it is acceptable to consider how uMrd might be helpful to the individual with their unique treatment goal(s)". (my emphasis)
At that point, better to throw one's efforts into bespoke care, and not try to see how many iterations one can sell to throngs of patients hopping from modality to modality in disappointment.
Great idea PulsedTherapy! There're a bunch of docs and scientists thinking along the same lines. It's been tried (and being tried) in other cancers. Here's an outline of the approach you might thinking of:
Wow, I feel like some kind of vindication for my "crazy" idea. It was so crazy, at least a pair of researchers had the same idea first, back in 2006, and have been working on it ever since. Here it's prostate cancer, but it sure seems like CLL would be an ideal candidate for a trial of the -- don't beat the disease down so far you create a dominant drug resistant strain, just beat it down enough, so that even if you do develop a resistant strain, the rest other strains stay in metabolic competition. The summed it up perfectly here, much better than I did:
"In a clinical trial with prostate cancer patients, one of us (Gatenby) tried an alternative to the scorched-earth approach, applying only enough chemo to keep the tumor tiny without killing it entirely. The goal was to maintain a small population of vulnerable chemosensitive cells. That population did well enough to prevent cells with an unwanted new trait—chemoresistance—from taking over."
Thanks so much FlyFish21, this was so informative. Maybe CLL treatment has been wrong for years.
Certainly not crazy to want a less aggressive treatment option. My husband was in awful shape by the end of his treatment, so my only reluctance to a staggered approach is having to undergo the same level of intense treatment on a recurrent basis. But a shorter treatment duration with fewer side effects and limited risk of mutation or treatment resistance?? That is the dream:). His doctor even admitted that his 4 cycles of chemo was 'really going for it' and recent trials had suggested that it wasn't necessary.
V+O has only recently been approved for CLL treatment, so it's possible that the protocol will be adjusted in the future. I think it's just more complex to alter because unlike solid tumours, CLL is essentially millions of tumours continuously being produced by your bone marrow. So, it can be difficult to detect, monitor and eradicate in contrast to tumours that can be permanently surgically removed or irradiated.
I remember that while initially researching CLL after my husband's diagnosis, I did wonder why CLL couldn't be treated similarly to the way HIV is treated, since they are both essentially diseases of the immune system.
I've discussed this with my specialist, and told him I am not interested in "going for the cure". I want reasonable control such that my quality of life is OK.
If I were in my 40's or 50's I'm sure I would think differently, but I'm 65. As long as I'm not in pain/uncomfortable, and can reasonably take care of things, that's great. This also helps me think of slowly increasing limitations as what I would be experiencing from "normal ageing", things that would change anyway as if I didn't have CLL.
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Yet another question 
Frivolous non-medical question! 
Question about lymph nodes 
To treat or not to treat, that is the question..
