Hi, as a relative newbie here, please forgive me if this is a really naive question. I am soon to begin treatment with a BTKi drug. I know that having (a mutated form) of CLL means that my immune system is significantly suppressed and that BTKi treatment will further inhibit the immune system. My haematologist implies that the treatment may well result in remission for a significant period yet I’ll still be taking the BTKi then. Does this mean that, even during that possible remission period, still taking the BTKi medication will continue to suppress the immune system, presumably because it also targets other cells? I have no idea what a typical plot of immune system efficacy versus time might look like. Thanks if you can enlighten me. And thanks to you all - as a regular reader, I have learned a lot, but not enough obviously! 🙂
Immune system changes during BTKi treatment - CLL Support
Immune system changes during BTKi treatment
Hello & Welcome to the group no one wants to join. You are in a great place for answers. I understand that our immune system is compromised from the CLL and then the cBTKI Therapy further immunocompromises us. What I am not clear on is, are you taking 2 different treatments? Because that is how you obtain durable remission. But remission is for a medication holiday so why would you still be taking something?
All I can really add from experience is to notify your doctors of any adverse reaction quickly. I could not tolerate full dose of Zanubrutinib & it took a while to reach that understanding. I wish you well on your upcoming adventure 🙋🏽♀️
No, I’ll probably be on Acalabrutinib monotherapy. My understanding is that I’ll be taking it continuously until and through remission and until it stops working, when another treatment approach would be selected. So does this mean my immune system will always be compromised by the Acalabrutinib itself even during remission when presumably my lymphocytes etc might hopefully return to being undetectably different from normal? Have I got the wrong end of the stick, as you suggest? Does monotherapy not result in a form of remission? Do you really need two-drug treatment to reach remission? And are BTKi treatments not continuous and long-term? I’m even more confused now!
Acalabrutinib inhibits all B cells, so that they undergo apoptosis, rather than maturing into immunoglobulin (antibody) producing plasma cells. That means you are unlikely to gain antibody protection from infections or vaccinations. You still get a T cell response from vaccinations and infections, plus the immune suppressing effect of CLL is lifted. Neutropenia is also common with all CLL treatments, which can make us more susceptible to infections, particularly bacterial, as neutrophils are our primary initial defense against infections.
BTKi drugs being a maintenance therapy, the aim is to keep CLL under control, rather than eliminate it. Only 10% of those in an ibrutinib clinical trial achieved uMRD after 4 years.
Neil
Thanks Neil. Your reply is much appreciated. The key point that struck me is that my treatment is primarily for maintenance of health and for control of the CLL, not for its elimination. However, I am told that the majority of patients with relapsed or refractory CLL treated with Acalabrutinib monotherapy remain alive and free from disease a few years later. That’s good enough for this 80-year old! Your statement referred to below by lankisterguy says that treatment “will eventually improve our immune system, so that it is generally better than what it was during watch and wait.” Again, good enough for me! So the picture of a time-plot I have got from you is of a dip in immunity after treatment starts, rising to some kind of plateau at a level higher than when I was on watch and wait. Right?!
Exactly!
Hi Fogey,
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You can find some excellent answers to your question from AussieNeil in this discussion:
healthunlocked.com/cllsuppo...
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My limited understanding is that with CLL we are all immune compromised, but not the same amount. Due to the incredible complexity of the immune system - there are no easy ways to measure how much. Low levels of IGG, IGA and IGM indicate some degree of low immunity but not for all CLL patients. Low levels of CD-4 T-cells is another indicator.
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There are hypotheses being tested, that over time the BTKi drugs like ibrutinib / Imbruvica, acalabrutinib / Calquence etc., may have a slight beneficial effect of improving our T-cell function, but that is not a clear or complete answer.
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Len
Thanks, Len. Interesting facts and an excellent link to AussieNeil’s previous summary. I’ll now look out for the IGG,IGA, IGM & CD-4T data. Best wishes.
Hello Fogey. I think part of the confusion stems from the fact that the definition of remission can be a moving target with cll. As of now, for most people Cll remain incurable. Some people were probably cured with fcr (chemo), but fcr, in general, can carry a higher risk of bone marrow damages than other new treatment.
They can run tests on our blood and or marrow to look for minimum residual disease (mrd), any evidence of cll. In some clinical trials, the definition of remission is where no cll cells at all can be found on the most sensitive mrd testing. People who got mrd negative with fcr turned out to be the people most likely to experience 10 yr plus remissions and be functionally cured.
Mrd negativity has therefore become somewhat of a holy grail of cll trials with the newer drugs like btk drugs and venetoclax. While zanubrutinib on its own is not likely to get one to an mrd negative remission, combining it with other drugs can. The hope is that mrd negativity with the new drugs will produce as durable remissions as does fcr for some folks. the jury is out on that now, not enough time has passed. We do know that getting mrd negative on the new drugs is no guarantee it will last, as some people who got mrd negative are relapsing after a couple years.
The new thinking with btk drugs for some doctors is to treat cll like diabetes, a chronic disease that can be kept in check with daily meds. Indeed, if you are 80 years old and just starting a btk drug, it might be the only cll drug you ever need and you might live out your normal lifespan or even better.
Outside of a clinical trial, remission can be defined as simply having normal blood work. If your wbc, hemoglobin, platelets, etc all return to normal limits with btk treatment, some doctors will consider you in remission even though mrd testing would probably still show some % of Cll cells.
Your danger at this point is that even though your cll stays under control, you might be at greater risk of infection due to a suppressed immune system. Thats hard to predict. Most everyone loses some immunity as they age. And as others pointed out, our immune systems are complex and have some redundancies built in.
My takeaway is that at your age, your doctor may think zanu is all you need. With each drug you add, you add toxicity risk. I find that with people starting treatment much later in life, many cll docs lean toward a simple is best approach, use a btk drug that is tolerable and can keep you in a sustained remission, even though your cll is never eradicated. The hope is we die with cll, not from it.
Good luck with your treatment. It might be the only treatment you need as many people are 10 yrs out on btk drugs without relapsing.
Thanks, cajunjeff. Good of you to take the time to explain things. As a retired scientist, I’m familiar with the vaguaries of minimum detection limits and the semantics of “cured”, mrd etc.. As an 80-year old who’s been on w&w for nearly 2 years, I’m well aware that I’ve won the lottery of life and I’m exceptionally grateful. But reaching this age without tangible symptoms despite having been told that I’ve got CLL mutations is amazing. And puzzling. OK, my blood lymphocyte count is rising, doubling in less than 6 months, but, if it wasn’t for the medics, I’d say I was very fit and well for my age. Apart from the CLL mental stress, I feel great. No swollen lymphs, no enlarged spleen, no weight loss, no night sweats. Nothing too worrying showing on CT scans and heart echogram - just cruising happily along. I often wish I hadn’t gone in for that initial annual health-check after which blood cancer has become an albatross round my neck. Despite feeling fine, I’m advised that treatment may well be recommended starting in springtime. Why bother when I’m feeling good and enjoying life? I have many cardiac and respiratory issues in my history but these have all for a long time been effectively countered via medication. Why should I agree to start treatment and accept all the extra potential risks and side-effects and what would happen if I refuse? I know you don’t know in my particular case but does anyone have some general comments? Thanks again, everyone.
Thanks cajunjeff for the explanation above on remission being a moving target. My question is that if one still has very few CLL cells how can he still have a one or two year remission? Won't the CLL cells multiply exponentially in the absence of the treatment?
Not necessarily. Some people have more indolent cll than others. Some people stop btk therapy due to intolerance and they go months or longer after stopping their treatment with residual disease that stays somewhat indolent after being beat down by the btk drug. Other people see their cll flair rapidly after suspending treatment. People with favorable genetics seem to do best, but sometimes folks with unfavorable genetics are able to suspend therapy and do okay for a while.
I think as general rule, outside of some clinical trials which have set protocols, doctors will maintain patients on btk therapy as long as they tolerate it and not take the chance of stopping. A lucky few will get mrd negative from btk therapy alone and can discuss with their doctor the advantages and disadvantages of stopping. Again as a general rule, if one stopped btk or venetoclax for reasons other than resistance, they can rechallenge their cll with the same drug.
Thats just my lay understanding, I could be wrong for sure.
Remember that as Cajunjeff notes, "for most people Cll remain(s) incurable", but importantly, CLL cells do die, it's just that they multiply faster than they undergo apoptosis. It's that difference between how fast they multiply and how fast they die that determines their exponential rate of growth, expressed as the lymphocyte doubling time. If there's an aggressive CLL clone, then the time before treatment is again needed will be shorter.
This is where we need to understand section 5. Definition of response, relapse, and refractory disease, in the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 update:
ashpublications.org/blood/a...
5.1. Complete remission
5.2. Partial remission
5.3. Progressive disease
5.4. Stable disease
5.5. Treatment failure
5.6. Time to next treatment, progression-free survival, event-free survival, and overall survival
5.7. Relapse
CLL specialists begin to really take an interest in looking for confirming evidence that another treatment is needed, when our lymphocyte count has grown to over 30 and the doubling time is under 6 months. If someone reached uMRD4, that is under 1 CLL in 10,000 white blood cells and they had a WBC count of say 4. then it will take quite a few years for the multiplying CLL cells to double the WBC. Even with a doubling time of 6 months, it would still require over 13 doubling periods, or close to 7 years, before the WBC went from 4 to 8. If someone on maintenance treatment decided to take a drug holiday after getting their ALC down to say, 4, with a lymphocyte doubling time of 6 months, it will take about one and a half years for their ALC to exceed 30; 4 (at stop treatment), 8 (six months), 16 (a year), 32 (eighteen months). The other factors that can trigger re-treatment of course still apply, per section
4.2. Second- and subsequent-line treatment decisions (with my emphasis)
Disease relapse alone is not a criterion to restart therapy unless the disease is symptomatic (see active disease criteria). Asymptomatic increases of lymphocyte counts alone without other signs of progression are generally not an indication to restart therapy. Second- and subsequent-line treatment decisions should generally follow the same indications as those used for first-line treatment.
Neil
Many thanks Neil and Cajunjeff for your detailed clarifications
Fogey, to my understanding the decision of when to start treatment is informed by Cll treatment guidelines published in the iwcll. One of those triggers for treatment is lymphocyte doubling time. You have not said if your hemoglobin and platelets are trending down as well, often these three triggers (lymphocytes doubling, hemoglobin below 1O and platelets below 100) move in tandem.
Cll doctors use the guidelines, along with their experience and gut instincts, to have us treat at the optimum time. We dont want to treat when we are feeling fine and our labs look okay. Nor do we want to wait to treat too long, when we are really sick and not as strong and able to tolerate our treatments.
If your lymphocytes are doubling in six months, that alone would justify a decision to start treatment soon. I would imagine your doc will want to look at another set of labs to see if your lymphocytes are still going up too fast.
You have written that you have 17p cll with loss of ATM. The fact that these mutations are often associated with more aggressive cll might also be informing your doctor on starting you now before you start feeling sick.
It’s great you feel well now, thats a good sign. But your lymphocyte doubling is a sign your cll is on the move. Unless your doubling test was an anomaly, or unless you are one of the lucky ones who have very stable cll, left untreated you will likely see your hemoglobin and platelets drop and start to feel bad. And even though cll is generally slow moving, when it’s on the move and doubling lymphocytes, we can go downhill fast, as I did.
I waited to treat when I might have started earlier and developed a bad case of hemolytic anemia, perhaps triggered by my rapid wbc rise. I might have been spared that awful experience by treating earlier, who knows, all I can say is that I went downhill very fast and I have supposedly more favorable cll mutations.
You should definitely discuss your concerns with your doctor. It’s a bit like Goldilocks and the 3 bears. You don’t want to start treatment when your porridge is too cold or too hot. Your doc must think your Cll porridge is just right, if you will excuse my flawed analogy.
Hi cajunjeff. You certainly know how to communicate effectively with an auld Scotsman! I love your targeted porridge analogy! Note that my old golden retriever is called Brochan, Gaelic for porridge! I get your various good points and am delighted to say that they agree precisely with those of my haematologist, who I believe is one of the foremost in this particular country. My platelets and haemoglobin have just now fallen below the lower limit for normal humans but not yet near action level. Your comments, by mirroring those of my consultant, give me great reassurance that I’m on the right track. Can’t thank you enough and I wish you well. Who knows when exactly is the right moment to start treatment. In my case, we’re extrapolating the blood data and waiting until the winter Covid, chest infection and flu seasons are over. Seems sensible to me. Thanks again.
Sounds like a good plan to me. Retrievers are wonderful pets. They duck hunt with us in the Louisiana marshes and it’s amazing how excited they get to head out on the boat to the marsh and how they seem to love diving in freezing ponds.
I am on a btk drug now, acalabrutinib, that works great for me. We added venetoclax at one point because I wanted to chase a cure, or at least a long, med free, remission. I couldnt tolerate the added drug and am now back on acalabrutinib alone and I would sign the deal now to take acalabrutinib for life if I knew I would never get resistant to it. I think there is a good chance a btk drug will be the only one you ever need, starting at age 80. And you have good options after that , so I think you have a great chance to outrun your cll.
I hope your experience with a btk drug is as good as mine. I’ve had a few side effects over the years, but none that really stopped me from doing most anything I want to do.
Slainte mhaith! 
Yes, our immune system will stay compromised irrespective of where we are in our journey. To what extent, that's individual.
If uMRD is an objective you should have a short duration combination treatment.
Were you not offered short duration treatments? Did you reject them? Have you not discussed them with your doctor?
Venetoclax + Ibrutinib (tablet only, 15 cycles/60 weeks) or Venetoclax + Obinutuzumab (9 IV infusions, 12 cycles/48 weeks). Both show good results for m-CLL with 17p/TP53, with a potential for years of remission off treatment. Venetoclax ramp-up is 5 weeks of 4 and/or 3 days a week at hospital for blood tests. With your concern about immune system Obinutuzumab is probably not a good choice as it's quite aggressive on the immune system. They still give flu and COVID shots but other vaccines are put on hold until 12 months after the last IV of Obinutuzumab.
Ibrutinib being 1st generation BTKi has more side effects than 2nd gen BTKi. V+I may not have been offered with a history of heart problems. Blood thinners are also a problem.
Venetoclax requires good kidney function.
So far CLL14 is the only trial to show this difference and the small number of m-CLL with 17p/TP53 gives a poor confidence interval (CI). I extracted the data for CAPTIVATE FD, it has similar good results for mCLL with 17p/TP53 aberrations and a better CI.
With all novel treatments ATM/11q is not the bogie that it was. The latest report that the NHS NGS panel for bone marrow test refers to for ATM del prognosis is dated 2017 and can be ignored.
Acalabrutinib trial ELEVATE TN has very nearly the same PFS at 4 years as the short duration treatments, around 80%. At 6 years it's 62% overall. (cf. CLL14 at 72 months 53% overall but 72% for m-CLL.)
As Neil said only a few percent reach uMRD4 on BTKi alone. You have to keep taking it to keep the lid on CLL. BTKi isn't "forever", at 6 years on first line there are only 47% still on Acalabrutinib. There are quite high rates of intolerance resulting in stopping treatment on BTKi even for 2nd generation Acalabrutinib and Zanubrutinib. The number stopping for intolerance increases over time 15.6% @ 58 months and 18% at 6 years (14% stopped due to progression while on treatment). Due to limited exposure times, short duration therapies don't have this high drop out rate.
themedicalxchange.com/en/20...
ashpublications.org/blood/a...
Stopping BTKi for intolerance results in better response to 2nd line than stopping for progression. This is a very recent report, little over a month since presentation, December 11, 2023, a doctor that isn't a CLL specialist may not be up to date on this.
ash.confex.com/ash/2023/web...
There are other papers for Ven after BTKi and BTKi after Ven. All of these tend to show that a poor response on 1st line treatment is a predictor of poor response on 2nd line. They have high numbers of subjects that are difficult to treat u-CLL with 17p/TP53 aberrations and few m-CLL. Because m-CLL with 17p/TP53 aberrations are so few they just get lumped into one group along with those that are u-CLL with 17p/TP53 aberrations. The reporting of results for all 17p/TP53 aberrations as one cohesive group makes the results look far worse than they actually are for m-CLL and boosts the poor results for u-CLL.
Thanks Skyshark. I will digest your info in detail later. There’s a lot in it, for which I’m grateful. Of course short duration dual treatments were discussed and examined closely, I personally have opted for monotherapy firstly because I’m 80 years old, feel fine and another few years like this will do me fine. Very different if I was younger. But slow and continuous seems more consistent with my way of life than a one-off fast and furious combination treatment. Secondly, I live more than 100 miles each way of difficult unpredictable rural travelling from my consultant and from the treatment hospital. The initial hospital-centred combination treatment does not seem particularly attractive, especially as tourist-packed public transport for 6-8 hours return journey is best avoided, don’t you think. My haematologist is, I believe, a highly competent CLL specialist, whose lectures feature often on YouTube. She knows her stuff, gives me research papers just published, including the very one whose plotted data you show, and she agrees, also having closely examined my cardiac and respiratory histories, that BTKi monotherapy is the way to go. And, having researched the pros and cons myself (ex-uni professor), I agree. Many thanks for taking the trouble to answer. I really appreciate it. Best wishes.
Using public transport for 100 mile journey, it's extremely unlikely that you would get to the hospital in time for the 9am blood tests that Venetoclax requires.
Last week, I had to travel for 7 hours one way to reach the consultant due mainly to unexpected road diversions, then stay overnight in a hotel so that I could meet my consultant! Most of my consultations are by telephone and soon by video call. But, now knowing my situation, Skyshark, do you agree that BTKi monotherapy makes some sense?
I am treated at the Duke Cancer Center in Durham, NC. I started Brukinsa in August. I am now completing my fifth month on the drug. After about 2 weeks I experienced bad muscle pain in my lower back. Actually it was severe muscle pain. I had some blood work at that time. My neutrophils were zero then and my WBC was up from 221k to 348k. I was immediately placed on a strong antibiotic to try to prevent any infection. I was never sick. I had more bloodwork within 2 more weeks and my Neutrophils were back up and my WBC was way down. My WBC has continued to fall and I have a little pain in my knees, that’s all. I still walk 4-6 miles a day. Also my Hemoglobin has risen! I feel good and have much more energy. I was first diagnosed in January of 2018. I was on W&W until August 2023. I wish you the best of health!
That sounds like a great outcome at this point in time and I’m encouraged. I’ve read that muscle and bone pain can be side effects. Are you saying that yours are being regarded as temporary side effects of the Zanubrutinib? Great to hear about the energy boost. I fancy some of that! I haven’t yet finally elected for Acalabrutinib over Zanubrutinib. I saw some relative data suggesting that Acal had fewer serious cardiac issues than Zanu and as I have cardiac history I’m currently leaning towards Acal. Also perhaps Zanu has more issues with neutrophil drop? What do you think? My haematologist implies that I’ll be on regular antibiotics like Bactrim DS. Were you on these from the start or just when your neutrophils hit zero? Did you start Zanu on full or half dose?
Whatever, it all sounds very promising for you. Best wishes for the future and thanks for the encouragement.
Dear Fogey
Identifying with you and finding your concerns and the replies useful. I am 80 in early March and while I live near London (came from Canada in 1969), my husband is an 84 year old Falkirk bairn and a scientist--(Uni professor as well--Chemistry )--and we are often in Scotland visiting friends, etc.
What connected with me is your feeling well and being active, except for your lymphocytes doubling. Mine are not doubling yet but are getting close, and my Haematologist is talking possible treatment. I posted about this a little while ago and had some good responses.
You wrote that " My platelets and haemoglobin have just now fallen below the lower limit for normal humans but not yet near action level. " It is interesting that is what my haematologist is predicting might happen to me--and that I might become anaemic rather than have all the other usual symptoms.
Like you I feel blessed to have reached this age. There is certainly a challenge keeping fit however---"use it or lose it". No dog to walk---but my husband is a great hiker (needless to say --lots of Munro's under his boots) so gets me out. Eleanor
JEEA, a lovely reply. Thanks. I was Chemistry too (Glasgow Uni). Noone’s perfect! Isn’t it funny how our CLL can be different for different people? Yours and mine sound similar but who knows how they’ll develop in future. The main thing is that we both reached a decent age and only have a condition which has new effective treatments. And treatments that are ever improving at pace. I feel a bit of an imposter on this site as I feel so good healthwise but it’s so nice to learn here and to find fellow spirits. All the best to you and hubby.
Thanks Fogey. I agree with you. But non of us are imposters on this site. It is such a good site to share concerns and get information when we have doubts / worries/ uncertainties. There are always most knowledgeable and supportive results. I'm slowly learning much more!
I've send you a 'private message' in the Chat function--you and my husband may well know each other.
Wondering if you are battling snow just now--although a warm front seems to have descended. ....
Eleanor
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