I am very curious about CLL cell replication rate over time and was hoping to see if anyone had any sources for any info. The CLL14 study had some very good info, but not enough to fully understand the disease progression.
I seems replication rates tends to increase over time, and one of the indicators for treatment is a doubling every 6 months. I tend to think that this replication rate is tied to at least 2 quantifiable factors: genetics and pre/post treatment. Understanding replication rates in the context of both these factors may go a long way to understanding the disease.
On the pre/post treatment, I have a suspicion, and it's not based on any evidence, that's why I'm asking, that replication rate actually increases post treatment. I suspect this because cancer cells are always in metabolic competition. Pre-treatment, normal healthy cells help keep the CLL cells in check. With treatment, CLL cells are drastically reduced -- a good thing -- but to a lesser extent, so are good cells, hence neutropenia.
Along with the loss of good cells, so is the natural check on the CLL cells. So if you have a great result after therapy and achieve say a uMRD6, so you are down to say, 20,000 CLL cells (for example), even though it is a small number, it may have a high replication rate, or at least, higher than it was pre-treatment due to the loss of the natural check (or maybe other factors, perhaps the treatment itself selecting for high replication rate cells).
So some type of data using ALC (pre treatment, I don't think anyone would have MRD before) and MRD after would seem to be a good start. Anyone else have other ideas? So the data might look like this for example, and if I am way off, please feel free to offer any corrections. I'm still learning about CLL.
mTp53/del17/uIGHV TP53wt/mIGHV
initial 5.5e9/L etc ......
+3 mo 6.6e9/L ....
+6 mo 6.7e9/L
+9 mo 7.8e9/L
+12mo 15.0e9/L
+15mo 31.0e9/L
+16mo treatment V+O
+19 mo 1e9/L uMRD3
+22mo uMRD4
+25 mo uMRD6
+25 mo end treatment
+28 mo uMRD6
+31 mo uMRD5
+34 mo uMRD4
+37 mo uMRD3
....
Thanks for reading, I am grateful for the insights you've been providing.
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Interesting, because I know so very little, cell growth in my mind is rather elementary and cartoonish. I only picture a cell divide and the theoretical 1, 2, 4, ... .
Therefore, my essential question would be what is the mechanism of cell division v. CLL cell division aside from saying CLL copies a mistake.
I do not know if there is a variability in rate, what could answer for it? Unless, one hangs it all on deletions (one less part written correctly)? But that wouldn't account for trisomy where one actually is writing more, it would take longer. See unless I could read up on the how, my understanding is rather too simplistic to believe one does grow faster than another.
I can conceptualize the CLL cells not dying so building up that way.
CLL and biology in general is very complicated, but you ask good questions: what is the cell division mechanism. I will bet there are hundreds of factors intrinsic and extrinsic to the cell.
The intrinsic factors can be changed by mutations, and the extrinsic factors are a function of the microenvironment the cells are in. That microenvironment is teeming with cytokines and chemokines that promote and suppress cell the various cell functions including replication. So you have lots of tradeoffs, and as you can see the drugs and protocols keep changing, you can see no one knows what tradeoffs are best.
For example, you can take these drugs to beat the CLL down to uMRD, but on the other hand, you can create mutations and have serious adverse reactions. Another example, that I am talking about here, is you can beat down the CLL to uMRD, but at the same time, you are changing the microenvironment drastically, and you can be creating an environment that signals the CLL cells left to replicate at higher rates.
There's no way to model this from first principles, it's just way too complicated, that's why I'm looking for the replication data proxies to get a better idea of these trade offs in the real world. Thanks again for you comment.
A highly developed sense of curiosity tends to trigger questions that are hard to answer. PT, you're a (wo?)man after my own heart.
Each of us who have gone through the process, from DX to TX and beyond, can plot our lab results, as measured in peripheral blood, over time. If we've been in a trial we may have some milestone results for bone marrow too. In a random selection of say a hundred of us, you would see big differences in the trajectory of the disease from person to person, as evidenced by their ALC count plotted over time.
Patterns would emerge, as you suggest, based on CLL clone genetics, such that an individual whose clone mutational status was IGHV-M and del(13q) would be expected to progress more slowly from DX to TX than another individual with IGHV-U and del (17p). You would find, though, quite a lot of scatter on the ALC progression plot for a given FISH-based sub-population.
Your post-treatment progression model assumes MRD-directed therapy, which is probably the exception outside of certain clinical trials. Even so, the rate at which ALC increases after treatment must depend on how effective the treatment has been, beyond that which can be measured even by NGS. If FCR, for example, is capable of achieving remissions in excess of 20 years, then it FCR must have reduced clone concentrations to <<10^-6.
Perhaps one reason that post treatment progression tends to be faster than pre-treatment is that treatment selects fitter clones from existing subclones. Another possibility is that treatment has little effect (as far as we know) on the tumour microenvironment, which is ready and waiting to go again.
With regard to the term "replication rate", I think it can be misleading here. The number we can track is the ALC, and its rate of increase or decrease over a period of time is due to the difference between the death rate and the birth rate of the CLL clones. The aggregate difference in the clonal population is more usually called the CLL "growth rate". Growth rate calcs need to account for the fact that the ALC count includes T-cells and NK cells, and that not all B lymphocytes are CLL cells. My own ALC growth rate holds steady at about 42 % per annum for 13.5 years from DX to TX. I'm IGHV-M, del (13q) and I hope it stops at that.
The dynamics of CLL pre DX is interesting, but inadequately researched. With NGS, the practical limit for detecting a CLL clone in a fairly indolent case (ALC doubling time 2.5-3 years) is probably 20 to 25 years before DX. I have seen 16 to 20 years mentioned in studies of MBL. This paper ncbi.nlm.nih.gov/pmc/articl... is one of a few that attempts to categorise pre-DX growth patterns and give them prognostic value. I think there is somehting in it, but the absolutes can be disregarded as the database is 2006-16 when so many patients were still being treated with chemo and chemoimmunotherapy without reference to IGHV status and FISH analysis.
Very good points, helpful in understanding the complexity of the issues (heterogeneity), again tugs at the leash of individualized care rather than YAM (yet another modality). [Yes I made it up, it isn't copyrighted feel free to reuse with wild abandon]. 🙂
"A highly developed sense of curiosity tends to trigger questions that are hard to answer. PT, you're a (wo?)man after my own heart."
It's very tough to appreciate this when you're suffering from it, but the underlying biology, research, and treatments, are all absolutely fascinating. Although I'm fairly certain we'd all chose less fascination and less disease. It reminds me of Old Benjamin from Animal Farm, "God had given him a tail to keep the flies off, but that he would sooner have no tail and no flies."
"Perhaps one reason that post treatment progression tends to be faster than pre-treatment is that treatment selects fitter clones from existing subclones."
You nailed exactly what I'm interested in finding out about.
a) does treatment actually yield faster progression?
b) is it a function of different treatments? VO vs AV vs AVO vs FCR etc?
c) is it a function of the different karyotypes?
d) is that progression from increased replication or slow apoptosis rate?
"Another possibility is that treatment has little effect (as far as we know) on the tumour microenvironment, which is ready and waiting to go again."
I'm not so sure this is the case, and really is at the core of my curiosity. Does the treatment really NOT change the microenvironment? For every 10 CLL cells you kill, you're killing a normal cell too (I have no idea what the ration is, but you get the point), and we know this because neutropenia is overwhelming in almost all CLL treatments. It could be that reduced normal cells, even if less than CLL cells, actually has large effects on the microenvironment. Normal cells do work to suppress CLL cells. So I think this is a wide open question whose answer may make the case for shorter, low dose treatments, even if they need to be "pulsed."
"My own ALC growth rate holds steady at about 42 % per annum for 13.5 years from DX to TX"
That's very interesting, a doubling about every 2 years, about 4 times as slow as the treatment baseline of doubling every 6 months. You mentioned that is from DX to TX, if you don't mind me asking, what has the growth rate been since TX?
This, or you, are pretty much exactly the test case I was thinking about with my original post on pulsed therapy. You are on a nice stable trajectory, so you and your body are doing a fairly good job at controlling the disease. But 42%, although slow, after 13 years is a considerable number that I'm sure compelled you to seek treatment. When I look at this situation, in the guise of first do no harm, I would think you'd want to simply reduce the ALC to a reasonable number in a way that does the least amount of harm to the valuable growth rate stability you have.
Who needs uMRD with a stable replication rate of 42% per year. Just bring the ALC (and I know ALC isn't the best number, Flow Cytometry would be the better number to use) down to 1E9/L, and then just let it keep doubling every two years until you need to treat again.
Thanks so much for all the info and sharing those results, I really appreciate it.
The growth of CLL as measured by the clonal CLL population is the simplest and cheapest way to measure just part of the total tumour burden. It's much more difficult to determine the typically much higher burden in the spleen, some 500 to 600 other nodes, the bone marrow, liver, etc. There's also redistribution between these accumulation locations, influenced by tumour microenvironment (TME) signalling and who knows what else. Lots more study of the TME is needed, but it's difficult and expensive to do. Mouse models only go so far and any resulting hypotheses need to be confirmed in human studies. We know that steroids, BTKi, PI3K inhibitors and other inhibitors block adherence signalling that keeps CLL cells in the nodes and marrow, so they spill into the blood. There's also evidence that one of the components in CBD oil does the opposite - drives CLL cells from the blood, back into the spleen, nodes, etc. See: healthunlocked.com/cllsuppo... No doubt there are other substances with similar properties.
I've attached some of the plots from the Extended Data Figure 2. Growth kinetics of CLLs from the extension cohort from the paper, Growth dynamics in naturally progressing chronic lymphocytic leukaemia
See also my next reply, with figure 3 illustrating what influences CLL pathogenesis, from a paper by the German CLL Study Group 2023 paper, Role of the tumor microenvironment in CLL pathogenesis
Figure 3 from a paper by the German CLL Study Group 2023 paper, Role of the tumor microenvironment in CLL pathogenesis, illustrating drivers of CLL pathogenesis.
Neil
Understanding the complex TME signalling in CLL could lead to a CLL cure.
Bennevisplace, that link the the TME paper was excellent. It was really eye opening to see all the other treatment possibilities that may be coming up. Looks like the treatment landscape for CLL will be developing quickly. Especially intriguing is the T-cell and NK cell interactions. Thanks for posting. Here's a direct link to the pdf if anyone needs it:
a) does treatment actually yield faster progression?
I assume you mean progression towards relapse, following treatment. It's generally the case that TTFT is longer than TTST, however ALC does not determine when to treat, so to answer your question one would need to see ALC time series following treatment for a patient cohort.
I reviewed my own ALC progression. Time from DX to start TX: 13.8 years, ALC: 5 to ~200 x 10^9 /L, annual growth rate ~40%. TX fixed term 6 months. Time from end TX to present: 4.3 years, ALC: 0.3-1.9 x 10^9 /L.
b) is it a function of different treatments? VO vs AV vs AVO vs FCR etc?
BTKi monotherapy seldom achieves uMRD in blood. In many patients FCR can achieve uMRD4 and complete remission for 20 years or more.
Nicholas Chorazzi wrote several papers on CLL progression and cell proliferation in the period 2017-19, see iwcll.org/cll-digital-archi... This one insight.jci.org/articles/vi... finds that The measured average CLL cell proliferation (“birth”) rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%–1.04%); this decreased to 0.05% per day (range 0%–0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%–0.7%) prior to treatment to 1.5% per day (range 0%–3.0%) during ibrutinib therapy, and they were even higher in tissue compartments.
Thanks for sharing Bennevisplace. You're numbers are outstanding, congratulations, and give me my first data point too. I may be doing it wrong, but I calculated the growth rate DX to TX a little lower, 30%, (200/5)^(1/13.8)-1, and the TX to present as 53%, (1.9/.3)^(1/4.3). So, to the first order, seems like it falls into the increased growth rate post TX, although we know it's not that simple. Even so, the post TX replication rate seems reasonable and manageable, so that's still a great result.
Thanks for Chorazzi's papers, I'll check them out.
I don't follow your arithmetic. I'll check mine later. Cancel your post-treatment calculation, the ALC is within normal range and it's too early to tell if the small increase is due to recovery of bone marrow function or CLL relapse.🤞
NB I edited my previous reply to clarify start and end of treatment
OK I think I see where we diverge. You're assuming that 100 % of the ALC grows, while I assume normal B-cells plus T- and NK-cells make up a flat 3 x 10^9 /L (the normal range of ALC is oft quoted as1 to 4.8), hence in my calculation CLL clones = 2 x 10^9 /L at DX.
Of course it's only the clone population that grows, while the normal cell population is relatively static.
Maybe someone who has or is still participating in the study of Natural History of CLL at the NIH in Bethesda MD US could share their knowledge on this topic .
Thank you may04cc, that study seems perfect. I emailed the name on the study site, I'll let you know if I here back. Here's the study site if anyone needs it
Replication rates are individual and change with time. I don't sign up to the good cells keep CLL in check theory. Wouldn't we all like to know what keeps them in check 😁
I believe that AussieNeil has in effect demonstrated and echoed what is very well established, the variability and complexity of the problem is not to be contained in an algorithmic approach. Rather, individualized therapy must become the norm if the patient not the disease is ever to be cared for.
This flies in the face of of those who direct the $$$ they only look to care for the masses - whether through gov't i.e. taxes or for profit i.e. pharma, insurance, etc. The only help is the rapidly developing tech driving the cost of the tests need to craft a medical response for the medical end. For example, the cost of high end genetic testing is sub $1000, sometimes as low as $600 when a few years ago even rather well to do people would have been denied.
I guess one could ask, is it cheaper to keep looking for the algorithm, then to use the technology?
To develop an algorithm is to understand the process and may never be achieved. There are thousands of algorithms which are not robust but still very useful. I would go with keeping research for the cure and but knowing full well that the issue is complex and prone to trial and error.
Hi Big_Dee, I'm sorry my last question was rhetorical. If I look at Fig.2 of Neil's I see about 4-5 classes of response and 2 I'd call outliers. So, I'm not against research I'm for dividing the pie a little differently.
The best fit for any of us may very well be one of the 4-5 categories (think the 80/20 rule), so why not spend more in individualizing the treatment to dial one of those approaches in for the patient being treated now. Furthermore, more of the results from individually directed therapies toward creating trials that will enhance the outcomes. 🙂
I did not feel like your question was rhetorical and I feel any improvement is better than none. We are in a good place of research due the ease of tracking blood cancer results. I would gladly agree with the 80/20 rule. Blessings.
Thanks, interesting article. But it doesn't explain the explosion of cancer rates in the last few decades. I believe the "Cancer As a Metabolic Disease" research of Prof. Seyfried provides more insight. Plenty of his YT interviews are available. Including the press/pulse therapy he is working on.
Thanks for the info on Seyfried, I'll check it out.
I am not so sure thought that there has been an "explosion of cancer rates," versus we are just living longer now, and with the increasing age, it's cancer that kills us, rather than the hundreds of other things that plagued man before modern medicine.
Statistics disagree. Once you watch Seyfried you'll find out more.
I asked Aria (the inbuilt AI in my Opera browser) about the trend in cancer incidence rates in the US and here is the reply I got:
"Based on the real-time information available, the trend of the diagnosed number of cases of cancer in the US in the last few decades shows an increase in the number of new cancer cases annually. Here is a summary of the trend:
According to the American Cancer Society projections, about 1,918,030 new cases of cancer were expected to be diagnosed in 2022.
The number of new cancer cases annually rose from 1.3 million to 1.8 million, growing consistently nearly every year.
The 2022 annual report provides estimated numbers of new cancer cases, deaths, survivors, and information on prevention, early detection, and treatment.
For more detailed information on the trend of diagnosed cancer cases in the US over the last few decades, you may refer to the sources mentioned above."
I really love how I don't need to google much anymore. I just ask the AI and get a good summary in seconds.
Thanks LeoPa, I don't doubt the statistics. And yes, AI has killed google search. I use chatGPT, and it's great. It is actually excellent at giving CLL answers too.
I agree. This may be the solution to all the nonsense that is on the internet. All the conspiracy theories and propaganda too. Makers of AI can't afford to let it come up with idiotic answers to questions. So I expect the credibility of its answers to only improve because that will be a marketing edge.
I notice that in the U.S., the NCCN no longer lists lymphocyte doubling as a signal for treatment. The old iwCLL Guidelines from 2018 still do. I'm not sure when NCCN dropped doubling. I'll need to hit archive.org to compare versions of their guidelines to see.
I'm also interested in this topic, as I'm comin off of a really effective therapy, and am getting regular ClonoSEQ MRD6 tests plus Flow Cytometry MRD4 tests. I haven't worked out the conversion from B-cells by volume of blood to B-cells by count of WBC yet. But I think the Weizmann Institute paper(s) on the total mass, number, and distribution of immune cells that I recently posted about in a reply to you will provide the raw materials for the calculation.
Brian Koffman recently blogged on some oddities in comparing the various kinds of testing - ClonoSEQ MRD, Flow Cytometry (not sure if it was MRD, or CLL Diagnostic flow), and ALC:
"Surprisingly, my flow cytometry tests remained negative until my count on clonocSEQ hit 1,888/1,000,000 or almost 1 in 500. It should be positive at anything over 1 in 10,000, so the two prior readings should have been positive. They weren’t, and I don’t know why."
I think we need to understand some of the mechanisms of flow cytometry, because instruments differ, sample sizes differ, etc. I'll again put in a plug that the ideal test results should identify the instrument, it's firmware, and reagents used. Research papers will often list at least the instrument and reagents.
The FDA still allows labs to certify their own laboratory-developed tests. So there may not be a published paper documenting individual Flow Cytometry tests like there is for things like ClonoSEQ and COVID. Flow cytometer instruments often have papers comparing models, but often they are paywalled, I find, so only abstracts may be available. The number of such instruments is boggling. I'm slowly saving papers on flow cytometry advancements and theory. Some of us may be aware that MRD testing via flow can be 1 in 10,000 or 1 in 100,000. But how does MRD sensitivity relate to sensitivity of flow for diagnosis?
You're right to treat FC results with a grain of salt, there are definitely some known challenges especially after treatment. This paper goes over some of it:
The NCCN Guidelines I was referring to that dropped the lymphocyte doubling is the Clinical Practice Guidelines for physicians. It comes as just the Guidelines, or Guidelines plus Evidence Blocks for quality of evidence and side effects for the different therapies. It requires that you create a free patient email account to download it. The site only does Google Recaptcha, Google Tag Manager, and Google CDN Static cookies, but I use Ghostery to block even them.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, NCCN Clinical P ractice Guidelines in Oncology (NCCN Guidelines ®), Version 3.2024 — March 26, 2024
I can''t download previous copies via Archive.org, because of login re-direct prevents it.
I do have a copy of Version 4.2020 that does not mention lymphocyte doubling, either. The NCCN Guidelines Insights, Version 1.2017 also does not mention doubling. But it's a review of changes, and not the full Guidelines.
"Patients with intermediaterisk disease (Rai stage, I–II; median survival, 71–101 months) have shorter survival, particularly when other adverse factors coexist, such as a lymphocyte doubling time of less than 1 year."
Before the iwCLL Guidelines in 2018 mentioned doubling in 6 months, 12 month doubling was the thing in some older guidelines, but even the group updating iwCLL 1996 Guideines in 2008 mentioned 6 months.
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines
Blood. 2008 Jun 15; 111(12): 5446–5456.
But there are no references to how the time period was arrived at.
It's fascinating to see how far we've come, and how thinking has changed. I asked at today's CLL Society Zoom Webinar about the 10cm lymph node requirement for treatment that's still in place. 10cm is enormous, and cruel! I can only think the Americans unfamiliar with the metric system don't balk at it because they just can't visualize it. Older ones of us that remember 100mm long cigarettes can visualize it, though.
The iwCLL is long overdue for an update that would address both the risks of older CIT (Chemo-ImmunoTherapy) and the benefits of Targeted Therapies. Maybe they're waiting to see how the ELEVATE trial and similar early treatment trials work out. But I think my mantra is Quality of Life is more important than absolute Overall Survival.
Seymour, the Physicians NCCN guidelines Version 3.2024 still notes that the results of the CLL12 trial didn't demonstrate survival benefit for early treatment with ibrutinib, so a '“watch and wait” approach remains the appropriate management strategy for all patients, in the absence of disease symptoms.' With respect to lymphocyte count considerations, while the lymphocyte doubling time check has been dropped (and it's a pity we can't find where that happened, because the NCCN does very well explaining why changes were adopted by the panel), similar phrasing is used as in the iwCLL guidelines with respect to "Absolute lymphocyte count alone is not an indication for treatment in the absence of leukostasis, which is rarely seen in patients with CLL."
Indications for treatment with respect to nodes and spleen have been updated in the current NCCN physician version to "Progressive, symptomatic, or present bulky disease (spleen >6 cm below costal margin, lymph nodes >10 cm" matching the iwCLL recommendations. Both the NCCN guidelines and iwCLL guidelines imply or state respectively that it's the node's longest dimension/diameter which is under consideration.
Yes, the iwCLL guidelines are well overdue for an update. Perhaps the panel is waiting on long term study reports from combination fixed termed therapies to inform changes in treatment recommendations?
Sadly noted. CLL12 has been rightfully criticized on a number of points for comparing apples to oranges in various ways. Lessons have been learned on how to conduct such trials, and newer trials are in progress.
CLL12: a positive answer to a poorly phrased question
Blood (2022) 139 (2): 151–152.
CLL12 did not measure overall survival, as is commonly believed. It measured EFS (Event Free Survival)
"EFS (as defined by progression to active disease, initiation of subsequent CLL treatment, or death)."
The ultimate question of Quality of Life vs. Overall Survival was also not addressed. I think we need to focus more on Quality of Life as a target in itself, and measure Quality of Life outcomes in all trials. Some doctors agree with me, and have been doing that. Of course, we would have to still compare Quality of Life and Overall Survival, and make our choices.
Younger patients are at a particular disadvantage in that the Overall Survival stats cited often do not incliude them at all due to the historically late diagnosis of CLL in the past. They may be in their prime years, and more willing to trade some unknown loss of lifespan for the possbility of improved Quality of Life in the hopes that future treatments will solve the survival issue. Attention to the other factors limiting survival need to be part of the discussion, too. This includes assumptions based on what area we live in and who is included in the life expectancy stats.
Good conclusion by Professor John Seymour, Director of the Haematology Department at the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Australia;
"CLL remains an incurable and burdensome disease for most afflicted patients, and we must therefore continue to strive to improve our current management. Given the observation that clonal evolution, including acquisition of the biologically adverse features, such as TP53mut and complex karyotype, can emerge between diagnosis and initiation of first treatment,10 well-designed early intervention trials should continue to be pursued. However, careful selection of outcome measures that consider the longitudinal nature of the disease is critical."
Thanks for that CLL12 study on early treatment, I had been wondering about that. Here's another early treatment study, but I haven't seen any results posted yet.
The EVOLVE study is Testing Early Treatment for Patients With High-Risk Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), EVOLVE CLL/SLL Study
Seymour, that is really informative, thanks for posting. When you write, "Quality of Life is more important than absolute Overall Survival," it's hard not to argue with that. But it does make me think back to my original post on the pulsed approach. Yes, you aren't going to get uMRD6 with one month of low dose Venetoclax, but you also aren't going to suffer the sometimes severe adverse reactions you do on extended treatment. Thanks again.
Your 3 monthly progression though uMRD6 to uMRD3 is bit quick. People that appear back in treatment in a year after V+O have a very aggressive CLL.
Months = period x log(Delta rise)/log(2). uMRD6 to uMRD5 is a Delta rise of 10 (1,000,000/100,000), log(10) is 1 and log 2 is 0.301. so the time for a rise by a factor of 10 is 4 x (1/0.301) = 13.2 months. For your example the period of doubling for a delta rise of 10 every 3 months is 0.9 months.
I would expect that for unmut-CLL that doubling every four months will be around median.
Thanks Skyshark, I really appreciate the feedback, especially the math. Your numbers seem very reasonable. But if there is a 10-fold increase every 13.2 months, that's still a pretty high growth rate per year: (10/1)^(12/13.2)=811%. Can pre-TX growth rates be that high too. It makes me think that post-TX growth rates increase.
Aren't you assuming that CLL distribution in the body is uniform at all states/stages of the disease? And that blood distribution/numbers somehow exactly correlates with bone marrow penetration/concentration? As well as concentration in nodes? We know it isn't. Who knows why it may collect in nodes or marrow, or for how long, before spilling into blood, taking us "out of remission". Or why it may be there, more or less quiescent, then suddenly start to activate.
From what I have read, bone marrow and blood percentage correlation exists when the disease reaches a point/affects other cells lines or organs where it needs treatment, and during treatment. That's where the data indicating close correlation between blood/marrow comes from, end of treatment studies. Docs don't generally start trying to look at "doubling time" until the lymphocyte count is over what, 30,000? And other prognostic factors "affecting time to treatment" but exactly how, is still unknown.
That's a very good point SofiaDeo: how do you know where the bloody CLL cells are. I don't think you do. Although, I suspect the proliferating CLL cells are in the BM or lymph nodes and spleen, and not in the PB. This is why I always wondered why the put people through the invasive and painful BM aspiration, because who knows if that is representative of the disease. But, we are still left with trying to find a metric for measurement, and it would seem the BP, as inaccurate as it may be, seems about the best of bad choices. No matter where the proliferation is -- BM, lymph, or spleen -- CLL cells are spilling out into the PB.
Agreed, Except when they present more as SLL. I know when I was first diagnosed, grossly abnormal cells on top of recent labwork plus my symptoms made it appear I had an acute process. The PET showed increased activity everywhere, but not increased node or spleen size. The bone marrow biopsy showed almost complete infiltration. I am just happy the flow and FISH came back as CLL, not an acute leukemia.
I think if a patient is having certain symptoms or lab values, looking at the marrow can be helpful. Mine told me I likely would need treatment sooner rather than later, even though the other cell lines had yet to drop below normal. By the time I arranged my first treatment & started it, a few months later, even if I didn't have physical symptoms my platelets &RBC & neuts were dipping.
A bone marrow biopsy isn't routinely recommended, and with 1/3 of us never needing treatment, I don't think it's needed for mild/indolent disease. Someone who got a diagnosis as part of a routine physical & remains asymptomatic with little variance in other cell lines doesn't need one. But someone having more problems, it may be smart to take a look, see what's going on in there.
Studies will always want things like BMB and CT and who knows what else, because they are trying to gather as much baseline data as possible. At some point, these data points may be clinically significant, IMO.
Before treatment I had 75% BM infiltration. Nodes were everywhere above and below diaphragm with a 14x21cm mass in my abdomen and ALC 86x10^9. Treatment started due to lymph nodes.
ALC is not a key to treatment, there are people on here with ALC of 400 and trials report up to 500.
It's when they start playing sardines in the lymph nodes, spleen etc or crowd the bone marrow resulting in loss of platelets, red blood cells etc. Also they don't mature to become plasma or memory-B cells.
If the ALC was the problem they could just be filtered out in a few hours every few months. Just like they collect stem and T-cells. Yes it's been tried and is still done in an emergency when the ALC is considered too high for successful pre-conditioning for SCT or CAR-T.
We only have 8 mentions of leukapheresis (filtering out lymphocytes from your blood) in nearly 40,000 posts, with only a few of those posts where members actually report having had this treatment healthunlocked.com/cllsuppo... It's rarely done with CLL, because the peripheral blood is soon repopulated from the CLL tumour elsewhere.
As the iWCLL guidelines state at the end of section 4, Indications for treatment; "Patients with CLL may present with a markedly elevated leukocyte count; however, the symptoms associated with leukocyte aggregates that develop in patients with acute leukemia rarely occur in patients with CLL. Therefore, the absolute lymphocyte count should not be used as the sole indicator for treatment." There's no ALC threshold mentioned in the iwCLL guidelines for initiating treatment either.
We have some members in watch and wait with ALCs of 500+, with some reporting ALC results of 800+ after starting BTKi treatment. Professor Thomas Kipps reported seeing one CLL patient with an ALC of 1,400. healthunlocked.com/cllsuppo...
Neil
CLL/SLL cells (dark) are nearly all nucleus and only slightly larger than red blood cells.
That's fascinating Neil. Just when I thought I was starting to understand CLL, you find out it's so much more complicated. I guess I immediately ran to ALC because that's the statistic that sets the ball in motion. From there to TX, like you say, it's an entirely different set of metrics. Thanks for this, very clarifying.
As bennevisplace noted earlier, read the study papers by Nicholas Chiorazzi et al
feinstein.northwell.edu/ins... The heavy water CLL research led to ground breaking understandings of CLL pathogenesis. Prior to that research, it was assumed that (a) CLL cells were immortal and (b) that their activity in the nodes was the same as was observed in CLL cells extracted from peripheral blood. (It's much easier and cheaper to take a blood sample than to perform a node or bone marrow biopsy). The dormant nature of CLL cells in the blood was assumed to also reflect their level of activity in the nodes and marrow, where the tumour micro-environment is so very important. This is also why in vitro research into possible treatments for CLL, is only the first step in checking how something might work in the body - provided you can get a high enough blood serum level that won't be countered by the CLL cell's tumour micro-environment protection mechanisms.
The Streetlight Effect is also why nearly all the COVID-19 vaccination studies look at antibody/immunoglobulin responses; it's way easier and far cheaper to measure immunoglobulin count changes, rather than searching for T cells which lock onto peptide fragments derived from SARS-CoV-2 viruses, presented on the major histocompatibility complex of virus infected cells ncbi.nlm.nih.gov/books/NBK2...
In the 'publish or perish' world of research, it's far easier to get funding for quick to produce papers that don't require expensive equipment and research laboratory supplies.
Neil, what you have pointed out here is of profound importance. It means we should be careful how much significance we attach to research papers, however esteemed the author and journal. Also it kyboshes the notion of science as a pure endeavour separate from the grubby world of commerce.
CLL cell proliferation (“birth”) rate was 0.39% of the clone per day (range 0.17%–1.04%)
Death rates of blood CLL cells 0.18% per day (average, range 0%–0.7%)
for patients whose disease requires treatment
"The measured average CLL cell proliferation (“birth”) rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%–1.04%); this decreased to 0.05% per day (range 0%–0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%–0.7%) prior to treatment to 1.5% per day (range 0%–3.0%) during ibrutinib therapy, and they were even higher in tissue compartments."
That was an exceptional paper Hervec, thank you! Using heavy water to make the calculations on CLL replication and apoptosis is brilliant. Put the numbers together, untreated the growth rate (replication - apoptosis) is (.39-.18) .21% and with ibutinib (.05-1.5) -1.45%. These are great metrics to use for modeling.
The paper also made some very interesting points on the sensitivity of uIGHV and mIGHV to ibutinib. Ibutinib seems to release CLL cells from the BM and lymph into the PB, but uIGHV is much more sensitive to the BTK inhibitor and you don't see the initial rise in ALC (supposed the uIGHV are already dead).
This was so good, did they follow this up with the same analysis for ventoclax? I'd think this would be standard protocol for all new drugs.
And while this is great data for before and during treatment, it didn't have data for post-treatment, something else I'm particularly interested in.
Replication minus apoptosis rate without ibutinib: .39%-.18% = .21%
Replication minus apoptosis rate with ibutinib: .05-1.5= -1.45%
to model what a hypothetical pulsed therapy model would look like (see graph).
Here I modeled 2 weeks on the therapy every 4 months (2 weeks on 14 weeks off) and you can see that the CLL count remains controlled.
It's my hypothesis that an approach like this would have:
1) far less chances of adverse reactions
2) far less chance of CLL developing selective resistance
3) and hopefully, a better quality of life and longer term survival.
With an combination therapy of venetoclax and ibutinib, or one of the newer BTK inhibitors, I suspect the replication rate minus teh apoptosis rate of -1.45% might be considerably higher. And if so, the pulsed therapy approach can have even short treatment durations and longer non-treatment durations and still keep the CLL count controlled.
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