Michael J Keating et al Dec 2019 - ASH oral presentation
Here they report updated data for the 80 pts with focus on MRD results.
After 12 cycles of the combination, 45/69 (65%) achieved BM U-MRD remission. After 24 cycles of the combination, 23/29 (79%) achieved BM U-MRD remission.
A total of 12 (15%) pts have come off trial. Five pts came off trial during IBR monotherapy [skin rash, n=1; hypertension, n=1; prohibited medication, n=1; unrelated infection (cryptococcus), n=1; withdrew consent, n=1]. Seven pts came off study during the combination phase [recurrent neutropenia, n=2; DLBCL transformation, n=1; pneumonia, n=1; fallopian tube cancer, n=1; allogeneic SCT, n=1; hemolytic anemia/MDS, n=1].
Note: 54% pts had dose reduction of IBR; 29% had dose reduction of VEN.
Conclusions: Combined IBR and VEN is an effective chemotherapy-free oral regimen for pts with high-risk previously untreated CLL.
Thank you Jackie for posting and summarising for us all yet another really interesting uptotheminute research result. Your knowledge and expertise is so valuable to so many of us on here.
I'm in this trial. I got in when they expanded it to 200 patients. Dr. Nitin Jain is my Dr. and the lead researcher. At 12 mos I am MRD 0.02% or 2 CLL cells in 10,000. I still have a year to go hoping to get to MRDU, but I haven't really improved that much since 6mos when I was 0.08% MRD.
Jackie these results are absolutely stunning when you look at the high risk patient population in this study. 83% have unmutated Cll!
We have had a few new members post recently who are understandably concerned about having high risk cytogenetics. This study is a great illustration of how novel drugs have leveled the playing field for all flavors of Cll.
Will all these patients reaching undetectable mrd status have durable remissions? Well that’s the big question. In the FCR chemo trials we learned that mrd negativity was the biggest predictor of length of remissions. So there is certainly reason to hope that holds true with the new drugs too.
Jeff my wish is to be on a drug that will hold for ever without relapsing because my biggest fear is exactly that. I spoke to the nurse at Dr. Lamannas office (she's so sweet and understanding) she said that my numbers are good, except for my wbc that is going up 20,000 more every appt (3 months) and that's y they predicting I'll be needing treatment end off next year.
Sushi when I start worrying I immediately, as best I can, try to put my worry to the test. Is there something I can do to change or improve things? If so, figure out what I need to do and get proactive. Those who say worry is a bad thing ignore the fact that worry can be a call to action. If I am not worrying about my test coming up, I am less likely to study for it.
Where worry is bad and harmful is when we worry about things outside of our control. In that case, worry robs us of precious time we could spend enjoying life.
For most people with Cll, treatments are cobbled together. One treatment is not often the only treatment we ever get. I am on ibrutinib and I know it’s probably not the only treatment I will need. But I feel good now and now is all there is. I can’t do any more than I am doing. If Ibrutinib gives me 5 or 10 years and I spend my time worrying I miss out on life.
You haven’t even started treatment yet and you are already worried about relapsing from a treatment you have not had.
I think there is a great chance for some a trial like this could be the only treatment they ever need. Or it might not be. This is a case where worrying doesn’t help spur us to action, it’s worrying about something we can’t change. That’s unproductive.
Suppose you take this combo. Now suppose it gives you a twenty year plus remission. Looking back, would you rather have lived those 20 years to the fullest or lived those years worrying about a relapse that never came?
We all worry. This is a thread about a treatment that has about 80% of high risk patients having amazing results. Don’t let your mind go straight to the 20% who didn’t do well and think that’s where you will be.
Jeff, i thank you for educating me on everything that i cannot understand it gives me more clarity. i need to learn to be more positive and leave the negativity behind me and to do that i have to stop worrying and be a worrier🙂.
Sushi the amazing thing about ibrutinib is that for those who take it as a first treatment, the survival curve at 5 years out is the same as general population. And for those that can’t tolerate ibrutinib, other options are emerging.
I personally think we are in the era where the majority of people diagnosed with Cll today will at a minimum be able to manage their Cll much like a diabetic manages his diabetes with a variety of diabetes medicines.
Best case scenario is we start seeing a lot of people cured. Either way, I predict ten years out from today you and I will still be on the forum here comparing how our puppies have grown.
I am also following the various reports just like you which provides me strength and courage to live but my eyesight is the thing not getting worse or better any way. God bless us all on this forum Amen
Yes it's not easy, they say to take it day by day.. And that's what I'm doing. I wish you well and hope u get the treatment u need to help your eyesight get better.
The answer to whether everyone who gets to MRDU will get a durable remission is we simply don’t know. Some people who don’t get to MRDU may also get a durable remission especially perhaps if their disease is slow growing. Of those who get to MRDU I’m sure some will have very long remissions but we don’t know how many at this stage. The assumption is that there may be similar long term results to MRDU however you get there. If we take FCR patients who achieve MRDU I’ve been told by a CLL expert that even those who are unmutated with FCR if they get to MRDU status then have approximate a ⅔ chance of getting to about six years or more without needing treatment and those who are mutated would have a higher chance than that of getting a long remission.
Only time will tell. But it would seem likely that the results may well turn out to be similar to FCR. Or who knows maybe even better. Certainly certain venetoclax studies have a higher proportion of people getting to MRDU than FCR ever managed.
Jeff, the thing about the FCR trial MRDU is that all those people were mutated IGHV. So the question is was it the depth of the remission alone (MRDU), or the fact that these patients were also mutated that gave them the long remissions?
The data I quoted of ⅔ getting to at least 6 years without further treatment was for those who were fortunate enough to get to MRDU with being given FCR despite being unmutated. (He showed me curves which I’m not sure if they’d been published). Those who were mutated did even better. The hope would be if you get to MRDU with a different medicine you probably will have at least as good a chance as those with historical FCR data though of course we can’t know that for sure at this point.
Sorry Adrian, I didn't see your post till after I replied. I've seen this data you posted before and I'm kind of using it as a guide of what to expect if I get to MRDU. 6 yrs would be pretty good if I could then repeat IV or if something better comes along.
Being on this combination on the Flair trial, I have good reason to be interested and delighted at these findings. I’m impressed at the level and frequency of data collected because my trial has yet to test my IGHV status and seemed to think my chromosomal profile wasn’t relevant as long as I wasn’t TP53. It’s always amazed me how the full range of testing doesn’t seem to be mandatory on Flair in order to assess the impact on different risk strata of chromosomal profile.
Excellent results and we can only hope that these undetectable results do indeed lead to very long, durable remissions.
Well stated Dawn. I suppose they had limited funds for their study. But Flair is such a large and important trial, it’s a shame they left out testing which would have given doctors so much more and important information that might inform decisions doctors have to make later.
I would think with all the grants and wealthy donors out there, they could have found someone to put up money for IGHV testing for trial participants. The Flair trial has so many participants, it seems a wasted opportunity to gather even more important data.
It seems that some sites do it automatically Jeff and I just think there should be consistency. Plus, how can the right level of data be obtained without this full range of information? As you say, the greatest reassurance from these combos is for people with high risk genetics to know they can do just as well as the low and immediate risk group. This particular study has also looked at next generation genetic sequencing like Notch & Birch for example which I don’t think Flair explores.
As the pharmaceutical companies are sponsoring these trials, I’d be surprised if funds were so limited.
Ask your site if they have the results back from Leeds yet from the flair genetic tests I believe these take a While but are complete. But my understanding is that it is the local sites responsibility to do TP53 mutation and 17p Del as a minimum before even considering using FCR in any context. We should name and shame and complain about any site not doing that as it is NICE required. And actually the company will pay for the mutation screening for any hospital who wants it even outside a trial if the hospital just signs a contract with them.
I’ve of course had the TP53 test Adrian prior to Flair application because it’s one of the main criteria for inclusion on this trial. They then re-checked. The FISH test wasn’t carried out automatically as I’ve discussed previously and it took me many months to have it done. The hyper mutation test has supposedly failed twice and there’s been no impetus in re-scheduling it.
My main point is that it clearly isn’t required as primary data for the trial which surprises me.
Actually I’m sure that they will use the mutation status in their analysis but some patients will have missing data points. At some point as your counts go down the test would be doomed to fail anyway and so they may feel that there’s no funding to try a third time. They would then leave you as a “missing data point” for this particular issue which is a shame but I suppose there will always be some missing data points. This is not a pharma company sponsored trial with all the regulatory bodies not breathing down the neck in the same way (and it’s done on a shoestring compared to the big ones). But even in big pharma trials we always have missing data Points at some point people give up chasing.
Do double check with your local research staff to ensure they have the results from the tests Leeds do. They definitely redo some tests centrally but they can take a Long time to send the results back locally (since they are in a sense meant to be rechecking certain tests). Not 100% sure which tests they do coz I can’t remember but one of them is may well be IGHV.
I do think though as well this is one of those do you want to keep pushing and make a fuss things. It’s hard to imagine a big specialist Centeral hospital like UCLH not just sending the test off a third time if you asked them to. But I bet UCLH even would forget to do it a third time if it had failed twice. We had something similar with me and the TP53 mutation test at the beginning and if I hadn’t insisted on actually seeing a copy shockingly they’d assumed they’d already seen the result at my first screening visit it was down to me to remind them that we’d sent it off again then!
We do have to be our own care Co ordinaators sometimes which is shocking really but unfortunately the case in many instances in whatever Health care system you are in. We have all decide to really push for something at times (even maybe to the point of putting in a complaint) but also have decided to let something slide.
My question for you is how much do you care about knowing this now? We know it can influence the choice of treatment but you are already on the better treatment if you have unmutated status. Your long watch and wait might mitigate against you having been unmutated since most of us need treatment quicker. And if you respond well to this treatment it may not make any difference as to how long you remain well.
But having said all that if it was me I Think I’d be pushing all the way on the basis that it’s unfair for you to be denied potentially prognostic information other nhs patients are allowed!
Your CLL lymphocytes. So if you did the test you’d have no CLL lymphocytes to identify whether they are IGHV mutated or not. Just like sometimes people run Flow cytometry (if they are doing the poor mans MRDU) and get confused because their clone has disappeared, or if they run FISH and find that they don’t have the mutations any more. Once you have almost no CLL lymphocytes around (see if you can beat Les than 1 in 500,000 which is where I got to (tho technically they can’t even report accurately at that level so I was officially less than 1 in 100,000).
It’s funny how often we all get confused about this at some point and I’m not saying you are but nobody ever told me that my deletions and mutations and IGHV status only existed in my CLL cells. It was ages before I asked one of my doctors in a slightly embarrassing way and they were like yes of course! But hey when we start our none of us know much about anything CLL related right?
For sure by the way we may all have certain normal genetic markers that made us more likely to get CLL but they are not the 17p and 13q Etc and just one of the glorious things about getting these cells as close to abolished as we can is that those wretched markers are no longer a concern (unless of course it ultimately grows back....).
And call me a simpleton while I’m at it but if you think that every time a CLL cell multiplies it has a small chance of evolving into something much worse (the dreaded richters) by making another error in copying DNA) well it seems to me that if we have millions of the blighters multiplying but then get rid of almost all of them you’d hope that we’d at least in theory reduce our chances of a richters transformation. Tho I have to confess I’ve not seen any data on that. But it will surely be one of the things in the future that we will find out more. Of course, this reduced risk would primarily show itself over time if we remained MRDU or at least with a very low burden of CLL cells. And when it comes to ibrutinib remember that whilst it doesn’t kill alll the cells in monotheapy it DOES massively slow them down from multiplying. So hopefully long term good treatments which work at reducing the number of multiplications may reduce the risk of New clonal evolution and richters formation.
Honestly there is still not enough data from FCR in the really long term (decades out) to know about some of these questions let alone some of the newer drugs.
Exiting days. Slightly scary days of course. But the Hope surely has to be that if we can get rid of or disable as many of our CLL cells as possible early on and stay that way as long as possible that can only be the best for us.
Even for current generation FCRers like me it is really a brave new world. Because most of us will only (at least in developed countries) ever have to do that once. And so we may well do MUCH better than our forefathers when if we do relapse we either go the ibrutinib or venetoclax/ rituximab route. (Or perhaps all three with AVO if that turns out to be the magic bullet).
One thing that excites me most about the AVO approach is that if you have three totally different drugs in there killing CLL cells in different ways (and driving them out of hiding places) we’ll surely it has to increase your chances of destroying any minor sub clones that are waiting to emerge that might otherwise be able to grow because of the single treatment you were on. Who knows if you had a tiny number of cells one day destined to become richters perhaps the rituximab type element would kill those off, whilst those that were destined to become an aggressive 17p del venetoclax resistant clone get wiped out by ibrutinib and those that were destined to become ibrutinib resistant get killed by venetoclax.
So much of all this is just theory at the moment. But every bit of data that suggests a possible benefit for using drugs together (and the data for VO and VI are BOTH really strong) moves us closer to forming a new FCR as if were.
I really really hope we don’t as a field get too confused looking for the short term gain. Take the Ibrutinib rituximab data. Some say it showed ibrutinib alone is just as good. But what if those patients in five years who has rituximab then turn out to have had less clonal evolution than the ibrutinib alone? Then we might potentially eat our words and say ah...it’s not just about how quickly you kill off most of the cells or even how long it takes till you need a second treatment. The real issue is do our treatments foster resistant clones or can we kill those before they have a chance to evolve. This was the idea of course of adding ibrutinib to FCR I’m sure in part (to prevent against FCR resistance emerging) as well as of course to drive cells out of the nodes to be killed.
You’re missing the point I’m making Adrian which is genetic testing for the trial does not seem to be a mandatory element in my Unit and we’ve had previous conversations about this where I advised that I’d had to take the issue to Prof Hillmen for clarification. Surprisingly, I am capable of exploring these issues with the trial team and it’s clear to me that it’s wasn’t a mandatory data issue unlike this trial Michael Keating has reported on.
I’ve lost count of the times you’ve questioned whether I had TP53 testing particularly as I couldn’t be in the trial without it.
I had a flow cytometry done less than 2 months ago when there was certainly enough residual ‘material’ for the IGHV test to be done. The issue previously seems to be a very borderline result in my case. I’ve decided not to pursue this further for personal reasons and not because I don’t understand the issues or am in some way incapable of representing my needs as your posts seem to imply.
Not trying to imply that you don’t know how to push for things or you don’t understand the issues. When I reply to someone I tend to think also of others reading who may not understand. I’ve learn so much from you and have huge amounts of respect for you!
In spite of Adrian's rather long post, I did learn something which I was not aware of. The CLL cells, which are abnormal lymphocytes, are the only cells with the genetic abnormalities such as 17p or trisomy 12? So these abnormal chromosomes are not in all of the lymphocytes, just the CLL cells? And after treatment, there might not be enough CLL cells left to test for genetic abnormalities any more?
That surprises me. I thought that my trisomy 12 was a genetic change which would be in all of my DNA. I thought that every cell has a copy of the complete DNA. I thought the trisomy 12 was what causes the abnormal formation of my lymphocytes, but that's not so? What does cause our lymphocytes to be deformed (if that's the right way to express it)?
A single lymphocyte is formed with at least one copying mistake (the deletion or mutation). It then multiplies and doesn’t die because of that mistake. And that mistake is only in the cancerous lymphocytes. There may also be some other more general genetic changes that made us more likely to form a cancerous lymphocyte in the first place but there won’t be for example 13qdel or TP53 mutation.
For sure without question venetoclax even in monotherapy is better than ibrutinib if your goal is getting to MRDU (in layman’s terms obliterating the disease) and then of course it allows a treatment feee spell. What is not yet fully clear is over say 20 years or more do you to better to use venetoclax in combo with obinituzimab or ibrutinib or maybe even both first, getting these remissions where you can then if in the future it becomes harder to get decent remissions switch to long term ibrutinib monotherapy to try and control not kill CLL or is it better to start at an earlier stage with ibrutinib for years controlling not killing and then only switch to an attempt to eradicate the CLL cells.
Which method will lead to resistance developing more quickly?
Which method will allow the longest time before neither ibrutinib nor venetoclax works
Hopeful that it may be a scientifically interesting but ultimately irrelevant question because so many people simply never get to the point where both of these medicines stop working (and who knows if even starting first with FCR just one set of cycles pushes that point even further back?). And in any case hopefully if we do find we ever get to a point where neither works there will be something else that does. There’s a suggestion for example that at least for some people who become resistant to ibrutinib acalabrutinib may even work and we know loads of other drugs are in development too.
Let’s say I and V (and maybe FCR) can all hold most of us at least 15 years between them (and maybe a lot more for quite a few of us!) the chances that we have lots of other drugs by then is very high.
Increasingly we are being faced with a good problem to have: not being sure which of the riches of drugs that all work to choose because we aren’t sure what will work best. We should remember it wasn’t so many years ago that there were no really good treatments at all. FCR opened the door to some people
Getting really long remissions and in many ways that wasn’t THAT long ago, and we are so blessed that so much else has come since or is hopefully coming down the line.
Certainly am enjoying the banter( scientific )and personal thoughts between AdrianUK and Newdawn . They are creating more questions then answers that we can ask our doctors.
My husband was determined to be MRD-U a couple of months ago after being on the fixed I/V trial and yes, it was a relief to hear that news at the time.....
...but, we also realize the each person's journey is a very individual journey so while we were grateful for the MRD-U status at the time, we've moved on from that and continue to take things one day at a time...one appointment at a time. Looks like we've made CLL a permanent part of our family until we know there is a cure.
Here's a lovely ASH 2019 abstract describing the rationale of this combination:
Ibrutinib and Venetoclax Target Distinct Subpopulation of CLL Cells: Rationale for Drug Combination and Implication of Minimal Residual Disease Eradication
"In conclusion, our study, comparing the actions of ibr and veneto in a clinically relevant CLL proliferation model, demonstrates for the first time that the drugs target distinct subpopulations of CLL cells with different proliferative capacity. The data also suggest that single drug therapy may leave a subpopulation behind that would potentially rise to cause a future relapse. Our study provides a strong laboratory rationale explaining why combining these two drugs has the potential to eradicate CLL disease. The findings are also in line with the clinical observations regarding the compartmental response; ibrutinib works primarily on the lymph nodes where CLL cells divide in the “proliferation centers” and veneto acts preferentially on the circulating CLL cells that are mostly non-dividing and resting."
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