This is how we achieve personalized, precision medicine.
73% of patients achieved U-MRD4 in BM after 12 cycles of ibrutinib + venetoclax. This is shown as the dashed vertical line.
Interestingly, the lowest U-MRD4 is the IGHV mutated subgroup. Hmm.
Slide from the oral presentation of this abstract:
ash.confex.com/ash/2019/web...
source:
60 out of 125 had mutated-yet 95 percent had undetectable mrd? deletion 13 was also to the left?
That's not how I read it. For the mutated patients, it appears to be an average of ~58% of them were U-MRD, less than the average of the entire trial (73%).
13q appears to be around ~63%, also lower than the trial average.
Very surprising to me that 13q and mutated both did "worse" than average.
what does the 95 percent at top of page mean?
That's 95% confidence interval, which is shown by the little horizontal lines for each subgroup. en.wikipedia.org/wiki/Confi...
So, I am both 13q del and mutated. My specialist said he would not treat me with Ibrutinb. I need to ask him a few more questions, rather than assuming it is just my age and familial history concerns. Not that I want to have Ibrutinib, just an oh! moment.
Also, there is more to 13q del that meets the eye. There are sub-clones related to that deletion that make it quite complicated. I have asked the RN at my specialists Dr. if they have done next-generation tests, she thinks they have. So I asked to have that information shared with me---not sure I really want to know.
The fact that 13q can be a slow-grow, doesn't mean it will, nor is the treatment path necessarily smooth or bumpy. There is a lot more to be known about CLL and there seem to be a lot of researchers doing what they can to be the discoverer of any key(s) to treatment---and for that I am grateful.
If you are in the USA venetoclax plus obinituzimab is now licensed and might be something you could discuss with your doctor. That or the AVO trial. Or perhaps even “old fashioned” FCR which can work really well. It would be great to discuss your future treatment with a CLL specialist who can explain the pros and cons of all the options available to you (including trials) and help you make an individual decision. Anyone who isn’t running CLL trials won’t have the breadth of up to date experience to help you know what is best for you as an individual.
Adrian, I have been told that is the treatment I will most likely have==there is more testing that I haven't seen, if it has been done, and we (Dr. and I) have only been speculating---so far it is not time.
The fact is that the subclone information is something that needs to be sorted for any 13q del profile, when and if that is possible. I am hoping the Nextgen that I have heard him say he is doing before treating any patients will help with that sorting.
He is on top of the situation and I just have to begin asking a bit more questions as they occur to me.
Gives me such hope reading results like this! 😊 very relieved to see no subsequent deaths in this cohort and only 3 progressive patients.
Newdawn
i went thru all the pictures on the twitter link, out of 164 patients initial patients only 3 had AFIB
Thanks for sharing !! These are fantastic results. One thought of caution. Do not read too much into subgroup analysis except that all subgroups did fairly well. Whether or not there is a significant statistical difference between subgroups is questionable. Typically trial design is such that subgroups are pre- specified prior to trials with the goal to see if there is a difference. This trial appears to be way too small to show that. Post-hoc analysis like in this trial raises interesting questions that need to be tested specifically in separate trials eg. are mutated patients worse off than unmutated with this combination and is FCR better for mutated patients. There are multiple phase 3 trials underway with FCR as one arm trying to answer this question.
I do agree we need to be slightly cautious about these sub group results. Tho the interesting point is that if you look at all the markers that predicted a bad result with FCR chemo they ALL seem to perhaps also at least potentially predict a better result for this new combination. I suspect therefore that if they’d pooled this data and defined two groups “high risk” and “low risk” this might well have shown a very dramatic trend for the “hi risk” group to be much more likely to do really well with this new combination than the “low risk”. (NB this is NOT the same as saying the low risk group didn’t benefit at all as we can benefit hugely from a treatment without ever reaching MRDU)
Perhaps there is something in all this, or maybe it is just chance. My hunch however is that if this a genuine issue it will be because we have defined these “high risk” and “low risk” markers historically on their tendency to be associated with patients who respond well or poorly to chemo. Thus for example perhaps a 13qdeletion might mean that there is a gene on that part of that chromosome that is sometimes associated with chemo resistance that is now missing and so chemo is more likely to work.
Thus the selection of some of these markers as high risk has been effectively to select for those with markers that can be associated with chemo resistance.
Since both ibrutinib and venetoclax are working in a totally different way to chemo, presumably there are different genetic markers that may possibly make this combination less or more likely
to work really well.
And so perhaps if you have markers that are associated with a bad response to chemo you are somehow statistically less likely to have the as yet unknown markers that may mean you are less likely to respond really well to I plus V. That’s one possible explanation of this pattern of results IF we think they are genuine and not by chance.
Or perhaps a more simple explanation might be that the more aggressive markers mean that your disease is growing faster and because of how much multiplication is going on it is somehow more easy to destroy more of the cells with this combo than if the disease is initially dividing more slowly?
Having said all this; the real take home message of this data is that ALL markers good or bad seem to be associated with a very good chance of getting a deep response and even MRDU with this new combination. The rates for none of these markers is “bad” and just a little while ago people would have been ecstatic to see even the lowest rate of MRDU after any treatment whatsoever.
Since most of us can’t get this new combo routinely yet we need to think about what we want to do in the meantime.
Some of us may have to or decide to do FCR first and let’s not forget other data shows that either ibrutinib/ acalabrutinib monotherapy does really well after a a patient has previously had a set of FCR (as well as firstline), or of course we can already reach for a Venetoclax combo first or second line depending on where we live (but most of us typically cannot yet get V plus I).
This new data combined with the amazing data for venetoclax plus obinituzimab makes the current A V O study for first line treatment very attractive indeed and I do think it’s worth many of us at least looking at that trial and whether it is possible for us logistically and whether it makes sense for us as an individual (discuss that with a CLL expert). And in the UK the FLAIR trial is almost as exciting!
It’s sometimes easy to allow all this data to confuse us, however, and get into endless debates about which treatment is “best”. It can almost feel paralysing! But perhaps we should instead appreciate just how fortunate we are to Have so much choice right now and such a rapid development of more and more data to help guide our future decisions.
As of today some of us who are fortunate enough to have Several options for our next treatment round. Unless we have certain specific reasons not to do one of these treatments we could almost just pull lots to help us make a treatment choice between FCR (tho most experts seem to now believe this should only be used first line if at all), ibrutinib monotherapy, acalabrutinib monotherapy, or venetoclax plus obinituzimab/ rituximab, and actually feel confident that whichever we got will probably help us. Then by the time we need any potential future treatment choice hopefully it will have become more clear what we should go for at that time.
One of the top UK CLL consultants said to me when he was explaining what my MRDU after FCR meant for my future (in the context of being UNmutated) he said “by the time you need treatment again we should all know what we are doing!”
Good analysis!
Hello AdrainUK
Yes, great analysis. We are much too different in our markers, comorbidities, both known and unknown to ensure known "best" treatment. I also suspect that as time passes that the greater population on these treatments, will revile changes or increases in side effects, much like ibrutinib. Blessings.
Here’s a video follow up with Dr Con Tam who delivered that presentation
onclive.com/conference-cove...
It’s very succinct. Read the summary article instead if you’re after any detail.
Those are amazing results , this sound be standard treatment now , no longer trial
It will be interesting when they determine why the 25% did not achieve UMRD, if they can. I am one of the 25%. And I am 13q, Unmutated, with a P53 deletion. Just finished 24 months on the combo. With so many different combinations and variables, it is amazing that this drug combination has worked in 75% of the participants! The folks that say Big Pharma is hiding a cure for cancer need to attend events like ASH and ASCO, to see all the work that is truly being done.
Hi Becky. Don’t think that it hasn’t worked at all just because you didn’t get to MRDU. Hopefully you have a much lower count now? Is the plan to continue longer on the combo or switch to ibrutinib monotherapy now or what?
Oh yes, my numbers are all good except for the ones that are kept a little too low because of the meds. The disease itself, is pretty well under control. When I did not reach MRD neg at 12 months, I was randomized to stay on both drugs, so will be on both until the trial is actually over. ( I think another 12 months or so). Even if I had tested UMRD this past Oct, which I did not, protocol stated I would have to stay on drugs til end of trial. I am just happy to have been a part of it, wish I was one of the 75% and also wish it had helped my immune system, but it has not. That is another variable in this disease which has not been studied enough yet and I wonder if the ones of us with wonkier immune systems have a harder time getting to the golden UMRD status. Who knows! Doc has finally put me down to 140 of the Ibrutinib to try and halt the GI issues. I think he doesn’t mind doing it now since he feels I have come as far along as I am going to. Interestingly, when I went on Wednesday, I had been off the Ibrutinib for 3 weeks due to my port placement and my ER episode and my platelets had jumped way up to above normal! White count was a little higher than it should be, but I do have a sinus infection that will not budge ( on steroids now). Lymph’s still very low but neuts doing well above the 2 level. But still catching everything that comes around regardless of precautions and IVIG treatments.
I might not sound like it but I am grateful for the positive effects of the treatment. Just feel a little bit like a kid on the playground not getting picked for the team. Not one of the chosen 75%. I am sure the data from the trial will eventually be used to try and figure out why the 25% did not reach the goal.
You could still reach it by two years! And remember many (maybe even most?) of people who do get to MRDU will probably still relapse after some time. And some of those who don’t if say kept on ibrutinib may not need any other treatment for years. It’s not so black and white as we tend to think sometimes!
I am on this trail unmutated 17 P deleted trisomy 12 complex karyotype and fortunately was able to get to U MRD after 12 months on the combo. I had a three months on Imbruvica to start the trial the both I plus V.
I am now 1.75 years off treatment.
I feel very fortunate given I started with such bad genetics.
Be well,
Hoffy
Fantastic news. Hopefully you have a really really long remission.
A GPO walks into a room and says, So it looks like you've got the better of the best of the good cancer.
Then out of nowhere Samuel L. Jackson appears and says "So What's in Your wallet?"
Apologies for the dark humor, however, there is a lot of encouraging news in this report.
Interested in what the twist with mutated is going to be?
JM
Update- My Imbruvica plus Venetoclax Captivate trial. This trial is going to reopen- Called CAPTIVATE. Ibrutinib plus venetoclax study sponsored by Pharmacyclics - Study Number PCYC-1142 . Upcoming CLL17 trial: (obinutuzumab + venetoclax) versus (ibrutinib + venetoclax) versus (ibrutinib monotherapy)MRD Negative in the bone Marrow for CLL / SLL after 15 Months on Imbruvica plus Venetoclax - Captivate trial. 
My 1 year CAR-T anniversary and from ASH 2018, Dr. Siddiqi on how CLL treatment has changed.
