I was just reading a new post in which the question was asked about number of years until relapse when on Ibrutinib. This raised a different question for me; although, reading the other post I'm thinking I know the answer.
My question is whether or not we stay on our first medication until relapse, or do we sometimes go off of it if we reach MRD. By the way I didn't know what MRD meant until recently (Minimal Residual Disease). I am still in Watch and Wait and hope I remain that status forever; however, realistically, I imagine it will be another year or two for me (currently Watch and Wait since February 2018. All this time I thought when we start our first medication, we stay on it only until we reach MRD. From reading this other new post today, it seems every person replying mentions having been on Ibrutinib between three and five years currently. Some of those mentioned reaching MRD a year or so ago. So from that I'm guessing that once started on Ibrutinib you never go off it; unless, MRD goes away due to relapse.
Am I now understanding this correctly, and when I ultimately go on whatever my first Novel Targeted Therapeutic is I'll remain on it until it fails?
Thanks as always for your input.
Carl
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wizzard166
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I'm not going to attempt to answer your question because I know we have members who can do that much better. But MRD... a can of worms if you ask me.
MRD on its own means that residual CLL cells are present. Those three letters need a pre- or suffix to express that you have so few CLL cells they were not detected. Then you are u(ndetectable)MRD or as some would have it MRD negative.
The Minimal part of the term was IMO redundant, and recently it's been proposed should be replaced by Measurable. So the term MRD remains intact. But then the "u" part makes no sense but "negative" does.
Following this?
Well, we're not quite there yet, because strictly speaking Measurable / Minimal can't be defined without specifying the method used to detect residual CLL cells - a newer method is 100 times as sensitive as the more established one. And there's something else we should specify: in which compartment are you looking for residual disease? Peripheral blood? Bone marrow?
I hope the experts will weigh in here and point you in the right direction!
Before inhibitors joined the range of treatment options for CLL about 10 years ago, all CLL treatments were of limited duration. That was in contrast to another chronic blood cancer, Chronic Myeloid Leukaemia, (CML) which was the first cancer for which an inhibitor was developed. The genetics behind CML developing is far simpler than for CLL and the introduction of Gleevec/imatinib pretty well changed that cancer from one with limited survival time to a manageable condition with near normal life expectancy. To achieve that type of breakthrough, you need a medication with a low side effect/adverse event profile where the medication inhibits the cloning process and there is a low incidence of resistance developing. (With CML - as now with CLL, there has been the development of new generation inhibitors for use if resistance develops.
CLL cells do naturally die through apoptosis, but the genetic errors which cause healthy B cells to become CLL cells result in the self cloning rate to exceed the rate of death through apoptosis, so CLL cells gradually accumulate. Research determined that stimulation of the B Cell Receptor (BCR) pathway in CLL cells prevented them from entering apoptosis. Over a decade ago, two enzymes were successfully targeted for inhibition in the BCR pathway, BTK and PI3K. Just after ibrutinib was developed to inhibit the BTK enzyme, idelalisib was developed to inhibit the PI3K enzyme. For a while it was uncertain which new drug would be the most successful, but clinical trials eventually demonstrated that Ibrutinib was the safer drug. Ironically, it was determined that idelalisib had a lower side effect profile in a second or subsequent line of therapy and it still has an important role there, with a second generation PI3K drug duvelisib in clinical trial.
So about 10 years ago, a new treatment paradigm for CLL (but not blood cancer) arose. Early trial results on ibrutinib determined that the drug worked slowly, with only about 10% of patients achieving uMRD after 4 years of monotherapy treatment. From experience with fixed term treatments, researchers knew that reaching uMRD was a good predictor for a subsequent long remission, but didn't know if that held for monotherapy treatments, or whether factors such as IGHV mutation status influenced this. That's what clinical trials like the UK FLAIR trial endeavoured to discover and for which we are still awaiting an answer. We do have community members who have stopped ibrutinib and are back on watch and wait, but we don't know yet whether that's a better approach than keeping CLL inhibited. Under which scenario are harder to treat sub-clones more likely to arise?
Eventually, we will know which prognostic markers indicate whether monotherapy or limited term combination therapy is the appropriate choice for a given patient.
To conclude this long answer, the above process highlights to me that "Big Pharma" does not dictate CLL management. If it did, watch and wait would not be the usual response to a CLL diagnosis and we would all be prescribed an indefinite therapy such as ibrutinib immediately. Ironically, it is those who seek an alternative therapy from proven treatments who are immediately started on treatments - usually indefinitely, to hopefully keep their CLL from needing "Big Pharma" treatment. When you consider that around a third of CLL patients never need treatment and the median time to first conventional treatment is around 5 years, after it was determined through past clinical trials that early treatment didn't extend life expectancy, that truly is ironic!
Interesting indeed that CLL patients are usually placed on watch and wait (worry) rather than immediately on drugs. This shoots a bit of a hole in "Big Pharma is pushing drugs" when in reality watch and wait is the general path that CLL doctors follow. Thanks again for the insight.
From what I understand, we are put on Watch and Wait because the benefits of early treatment are outweighed by the dangers of the side effects of the treatment.
That finding that early treatment didn't improve life expectancy was from decades ago. It's not only side effects from treatment, but importantly the higher risk of potentially fatal infections during and for some time after treatment. There are also the long term risks of secondary cancers and living with a degree of reduced bone marrow capacity, typically exhibited as lower platelet and haemoglobin counts and sometimes neutropenia, which along with low antibody counts, impacts on quality of life. Also, with far less treatment options, if your remissions didn't last that long, you would run out of options minus the potential years of watch and wait.
With the advent of targeted therapies, there were a few trials done to determine if starting treatment earlier was advantageous for some of us - in particular those of us at higher risk of progression (complex karyotype) or developing Richter's Transformation. This is another evolving area in treatment paradigms to watch.
When you say that the concept that early treatment didnt improve life expectency was from decades ago, it confused me; since, I've only been reading about CLL since my diagnosis in Feb 2018. I know I've read that concept quite a few times, but maybe it was only on this site from other members. What is the current day concept about early treatment?
I'm not up on the side effect possibilities, but I thought it included damage to organ systems and sometimes the brain. The list of things you mentioned, aside from side effects, is pretty scary; enough, to make me not want to start treatment for sure. I mean I realize I might have to do so at some point, but wow I hope I never need to start. Whats the deal with potentially fatal infections? Is this because our immune system is even worse when on treatment then when not on treatment? When we add low hemoglobin, low platelets, and reduced bone marrow capacity, it seems to me these are all the things the CLL Specialists look for to justify starting treatment in the first place. So I don't get it; why do they start treatment, if treatment produces the same warning signals that precede treatment.
In summary, we aren't there yet; quantitative indications for an earlier start to treatment are yet to be included in the relevant guidelines.
CLL suppresses the immune system in multiple ways and all CLL treatments can have an impact on bone marrow production. Hence the treatment commencing thresholds in the guidelines include a buffer allowance so the likelihood of needing red blood cell or platelet infusions is low when treatment starts. Interestingly, those treatment thresholds (haemoglobin or platelets dropping below 100), didn't shift with the introduction of targeted therapies.
As treatment begins to clear out the bone marrow, blood counts gradually improve, plus the CLL tumour burden's immune suppression effect gradually lifts. Unfortunately, healthy B-cells and with some treatments T-cells also drop, so our adaptive immunity suffers, plus neutropenia can be a problem. This can cause opportunist infections, e.g. shingles and pneumonia which is why prophylactic antiviral and antibiotic treatment is common during and sometimes for a while after treatment. This is why it is so very important to get up to date with non-live vaccinations as soon as you are diagnosed and then subsequently maintain them: healthunlocked.com/cllsuppo...
Thank you Neil, you are a tremendous help to anyone trying to understand they sometimes conflicting dynamics involved in when not to and when to start treatment. I think I understand now that the treatment can bring all of the problems like low hemoglobin and low platelets and weakened bone marrow back toward normal status; however, in a lower percentage of cases it can exacerbate those problems. The effect on the immune system is also confusing because it is different components of the immune system that are damaged when not in treatment, than those that might be a problem when in treatment. Whoa, heavy duty.
I have been on ibrutinib 4.5 years still in remission and I will continue to stay on it until it no lot works .the first 18 months although is often where people especially say in the US jump ship because of hearts fib, aches, acid reflux etc Here in the UK where are treatment is free and as a result done at cost they tend to keep you on the same treatment untill relasp .I myself had severe aches but worked through them first few months then it was blood pressure so got tablets for that then acid reflux so got tablets for that as well and I feel better then I have for years as a first treatment and if you see it through you could get 8 plus years there are still people on ibrutinib that long now and it could go longer as more time passes more data will be collected . I think that the 2 to 5 years mark is flawed as it includes those whose choose to come of due to the problems mentioned and try another drug often promted by there doctor and dare I say in the US money and drug companies play a huge part in offering people another option when maybe they could just stick it out on there first option if the treatment is working
So in answer to you question yes we stay on this wonderful drug for life or relasp
Yes I second other comments re long term use. I've been on Ibrutinib six and a half years and counting, with manageable side effects. Will not reach MRD with Ibrutinb - due to a 'quiescent clone ' but blood counts hover within a stable if somewhat abnormal range .
I don't know that I can answer that, I'll just tell you what I was told when I was given a prescription for Imbruvica. First I asked how much it cost, and the Dr. told me, nobody can afford it.....we'll help you to find agencies that will pay most of the cost, (and they did), and I asked how long will I have to take this drug, and he said, forever......think of it as taking a blood pressure medication or diabetes. I later found out, it's also until it doesn't seem to be working anymore, but that hasn't happened yet. I've been on this drug for over 5 yrs. now.
Hi , Same here, my Oncologist told me Forever (Imbruvica)Been on it 5 years it’s Protecting me from Leptomenangeal and CLL I’m extremely lucky as I have had very few side effects over the 5 years ...Cheers ...Vincent
I'm happy for you. We are lucky to never have had any side effects. My oncologist is always amazed that I've had none from the first day on. May it continue to be that way for both of us.
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