Can Venetoclax/Obinituzimab reduce the risk of additional somatic mutations? - Not necessarily. The BTK inhibitors are excellent at....

[lankisterguy]

Below is a repost from [e-mail] ( permission granted by Dr. Furman)

- I believe this hypothesis may be tested in a proposed clinical trial Dr. Furman has mentioned in the past- Len

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Can Venetoclax/Obinituzimab reduce the risk of additional somatic mutations?

From: ------ Date: Thu, 23 Jul 2020 14:25:18 EDT

Lately there has been a rethinking of the watch-and-wait (w&w) paradigm. Some CLL specialists are advocating treating high-risk CLL patients before they reach traditional treatment thresholds. Reasoning that the studies advocating w&w are based on chemo or chemoimmunotherapy, today’s novel agent treatments are believed to carry less long-term toxicities so there’s less reason to delay treatment. The benefit of earlier treatment is to minimize the likelihood that additional somatic mutations will occur in the CLL cells and lead to a worsening of the disease.

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Couldn’t the same argument be made for choosing a treatment that achieves u-MRD or minimal MRD over ones that don’t? For example, the time-limited Venetoclax/Obinituzimab combo typically achieves u-MRD (or nearly so) in most patients. The BTK inhibitors can also achieve this, but in a much smaller subset of patients. Wouldn’t it be advantageous to have far fewer CLL cells during your remission, thus reducing the chances for additional harmful mutations, even in patients without high-risk CLL?

Thanks, Dave

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Reply From: Rick Furman Date: Fri, 24 Jul 2020 02:11:57 EDT

Not necessarily. The BTK inhibitors are excellent at stopping proliferation, which would theoretically have an impact upon decreasing the risk for the development of mutation and transformation, both of which require proliferation to evolve. The same is not true for venetoclax/obinutuzumab.

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Ultimately, the only data we have thus far is comparing single agent ibrutinib from one study to single agent venetoclax (or venetoclax/obinutuzumab) in another study. The important read out from my perspective, and I assume most patients, is progression free survival (PFS). As long as your disease is well controlled and does not cause symptoms, and you are tolerating the treatment, you are fine. I have patients on ibrutinib for over ten years now who are not MRD negative (uMRD), but are free from progression. I suspect the PFS might be better for BTK inhibitors over venetoclax based regimens.

Rick Furman, MD

[Justasheet1]

Thanks Len. That’s not only informative but coming from Dr Furman it’s as good as it gets.

Jeff

[JigFettler Volunteer]

Thanks Len.

Hmmmm...

Makes me wonder about very low level B cell proliferation, and a trickle of a low dose BTKi.

A low dose to keep a small B cell population from proliferation. Fewer side effects...

Says me, who wanted I +V and got FCR. (UK England) ... but to good effect!

Jig

[bennevisplace in reply to JigFettler]

Me too. Do you believe Flair randomises subjects without regard to their genetic profile? I don't, though I have no evidence because patient information docs don't discuss the question and the medics are coy. It's obviously a sensitive issue where ethics should temper the need for clean data sets.

[JigFettler Volunteer in reply to bennevisplace]

FLAIR, as I understand, only would exclude 17p deletion in randomisation. Other parameters of course are employed.

My FCR was not in the FLAIR trial, because I would have lost my W&W Haem Team, with whom I had developed a good rapport. So I had FCR outwith FLAIR.

Why are your medics coy? Surely they should be open to any and all questions!

Jig UK

[bennevisplace in reply to JigFettler]

Yes, I recall that P53 mutation is an exclusion criterion, which covers 17p (?). But it doesn't cover IGHV unmutated (and other genetics?) for which FCR is already known to be less effective than targeted therapies. Isn't this an ethics issue? One way to deal with that is to stratify the randomisation process to prevent e.g. unmutated subjects being randomised to FCR. This implies a crafty randomisation algorithm to achieve an unbiased sample of subjects in each of the 3 arms of the trial. It also implies that if your CLL genetics make you a prime candidate for FCR your chances of being randomised to FCR are greater than 1/3.

To be fair to my medics I didn't probe deeply into it, but I felt that the study nurse was vague to the point of evasiveness.

[bennevisplace in reply to bennevisplace]

i.e. "the computer decides" . In my case the computer said no.

[Newdawn Administrator in reply to bennevisplace]

I was randomised to I&V on the Flair trial with only a single probe of cytogenetic testing having been done on the NHS to eliminate a TP53 deletion. No other testing relating to mutational status or chromosomal profile seemed to be necessary and I had to insist it was done. I thought it was done automatically but my Consultant said it wasn’t important once I’d been randomised to I&V! 🙄

Newdawn

[bennevisplace in reply to Newdawn]

Hmm, that seems less info than I received, Newdawn. Prior to randomisation I knew I was 13 q mutated. FCR-ready and sure enough that's what I got. Call me unduly sceptical if you like, but then I'll question your motives 😊

[Newdawn Administrator in reply to bennevisplace]

Not fully understanding what that means bennevisplace.

My medical team have never discussed my chromosomal profile and seem to overlook its relevance if I honest.

I was pleased to get on the I&V arm however regardless of my bio-markers.

Newdawn

[bennevisplace in reply to Newdawn]

Yes I+V seems a really effective combo and would have been my choice, FCR ready or not. I +V seems to cover the CLL mutation spectrum and perhaps yours were deemed not so relevant once you'd been randomised.

My haematologist definitely gave me the genetic details after screening and before randomisation to Flair. 13q deletion, no TP53 involvement, IGHV mutated. Interesting if on the same trial the order of events pre-treatment varies.

As I recall the haematologist was selling me the FCR story before I was randomised, I.e.

ashpublications.org/blood/a...

[JigFettler Volunteer in reply to bennevisplace]

13q mutated. Same as me. There is a group of patients that get a long remission. If in remission at 7yrs, 91% likely no recurrence. Sorry can't access the evidence... just now.

So... in 2018 I was steered to FCR heavily. Bear in mind I wanted I + V. FCR remained the Gold Standard.

Unmutated its gets less predictable.

75% of all CLLers, the experts tell us, will live out a favourable lifespan.

Trials are very important to show us all the way forward. My treatment opinion leads the UK FLAIR trials. Meant a lot to me when I was nudged to FCR.

A 5hr drive home from that 2nd opinion, I'd made up my mind.

Jig

[bennevisplace in reply to JigFettler]

Yes Jig, FCR is still the gold standard for our genetic profile, unless side effects are judged too harsh for a particular patient to handle. In my reply to Newdawn above is a link to the paper you may be thinking of.

There certainly is reassurance in being nudged towards FCR, in having a relatively favourable mutation and in being assessed as fit enough for that treatment regime. For us that's water under the bridge, but I'm still curious about me being nudged before being randomised.

Good health to you.

[JigFettler Volunteer in reply to bennevisplace]

I was nudged in same manner. Stand firm. Keep fit. Be strong. Above all be informed. This site is a great place to start.

ashpublications.org/blood/a...

This is a 2015 paper...a lot has happened.

Jig

[AdrianUK in reply to bennevisplace]

I think it’s important to understand fully the UK position. A clinical trial is considered ethical or not based on a number of factors. But a key one is what treatment would you get outside of the trial.

In the uk at the moment the funding body (_NICE) and professional opinion from the top CLL experts believe that the only groups of patients who should be excluded from FCR as a first line treatment for genetic marker reasons are those with a mutated or absent TP53 gene (17p deletion being the absence of that gene). Thus this group of patients are not eligible for FLAIR and all other patients deemed medically fit for FCR are eligible to be ethically included in the study. Your nurse may have been uncomfortable explaining this but the information leaflet clearly states that all people included in FLAIR have a random choice of one of three treatments allocated (FCR, ibrutinib, venetcolax plus ibrutinib). If they do not enroll in the study 100% of patients would be treated wirh FCR, thus making this entirely ethical in my view and more importantly the ethics committtees view

Whilst it is true that some other markers including IGHV unmutated status reduce the chance of FCR working, it CAN work. I am an example of someone who it has worked in. In September I will mark two years since starting FCR in FLAIR and so far there are no signs of relapse and I got to MRDU status with less than 1 in 100,000 cells being CLL and all my nodes disappeared. My lymphocyte count remains bellow 1 (thousand). I have been told that since I got to MRDU but am UNmutated I have a ⅔ chance of having more than five years before I need another treatment. If I was mutated this chance would be a lot higher and many do not need trestment for more than 20 years.

The other key ethical factor is that if your assigned treatment doesn’t work or if you relapse later on you are fully funded by NHS to have either Ibrutinib monotheapy or venetcolax plus rituximab second third and fourth line. There is no conclusive evidence that people who take only one course of FCR are very significantly less likely to respond to the newer drugs at the second line point than they would have been if they were given the drug initially.

Crucially FLAIR will follow patients in an environment where second line and beyond treatment is freely available wirh no funding restrictions and a reasonably standard approach (ie most people in the Uk should be offered a choice of VR or I at second presentation and beyond and are unlinked t to be offered anything else outside a clinical trial).

So really FLAIR is a study compairing three treatment strategies that each include access to the newer drugs along the way. We are asking the question and will answer it definitively - is there a group of patients who so better in the really long term (ie over twenty years!) by starting their treatment with FCR to delay or In many cases prevent the need to use the newer drugs.

It could turn out that if I get a five to ten year delay in starting the newer drugs thus might translate into a five to ten year delay in when the newer drugs stop working for me and so perhaps even a five to ten year longer life.

It could also be true of course that this life prolonging aspect if it happened might happen despite the fact Needed to start my second treatment sooner than I would have done if I started one of the newer treatments as my first option.

FLAIR of course may we’ll be the clinical trial that finally puts the nail in the coffin of FCR as a treatment option at all.

My own hunch? Well I think that chemo may remain an option for younger patients for some years to come. But if it is replaced my hunch is it will be replaced by a venetcolax containing combo as first line rather than ibrutinib monotherapy. It just seems to me implausible that starting ibrutinib before the age of 50 could possibly mean that it would be the only treatment you’d ever need as surely eventually it will likely stop working. (Even if that’s more than 10 years down the line for some). But that’s just a hunch. And without the really long randomised trial data we simply cannot tell what the truth will be.

[Cheshire2016 in reply to AdrianUK]

Patients being diagnosed younger may be an important factor in future treatment protocols.

We were dreading ever having FCR, mainly as most of the news on here is about newer treatments ( which is obviously what the trials are set up for)

But so far we are on cycle 4, and apart from slight nausea and tiredness on the 5 days of tablets, my husband is coping really well- still working and is out running 7-8k from week 2.

But I do wonder like you, why a treatment that works would be eliminated completely when younger patients might need a sequence of therapies to last their normal life span.

[bennevisplace in reply to AdrianUK]

Adrian thanks for this, much appreciated.

Encouraging that you are doing well after FCR. Your insights on FCR and FLAIR are very helpful. Following on, maybe you can explain 1. While you would expect randomisation to fill arms roughly equally, the 4th arm stopped recruiting very early because it had enough subjects (official reason)? 2. Why have I never heard of any FLAIR entrant with FCR-optimal CLL genetics being randomised to one of the other two arms?

Yours gratefully, in ignorance.

[AdrianUK in reply to bennevisplace]

1. The original study design was ibrutinib plus rituximab vs FCR. Then two more arms were added. But the way it is set up effectively each new treatment protocol is compared to FCR not each other (or at least not as the primary end point). So it’s simply a historical thing that the study is powered for a certain number to be in each arm. Thus when the IR arm was fully recruited it was dropped to ensure that there was an eventual balance to the study arms. As for whatever your own experience of the randomisations you are aware of I’m sure that’s just a random variation. It may be of course that some people who know they are genetically ideal for FCR are actually reluctant to volunteer for the study and so end up taking FCR out of the trial (especially earlier on). It’s very easy to see a pattern that isn’t there. I’ve been told that the randomisation is done by a computer and I am sure it is being done appropriately.

[bennevisplace in reply to AdrianUK]

Thanks Adrian, that covers it nicely.

[AdrianUK in reply to bennevisplace]

Just do you know by the way if you take the whole study from begging any one patient has about 1/4 chance of getting FCR so that might also explain your observation as well as the very human thing that if somethingn happens we are not happy about we are more likely to report it on something like this. I mean if someone got FCR and knew they had higher risk makers they are more likely to come on here and ask about it....

[Tapps]

Thank you.

[BeckyLUSA]

I am one of those Dr. Furman is talking about. I started treatment relatively early compared to many people. On an I & V trial and after 3 years, but have not reached MRD neg status. Due to side effects, my Ibrutinib has been reduced to 140mg a day. Since this was done in November, my disease is still well under control, numbers good, not progressing. I will take it! I go off of the Venetoclax in November. Hopefully the small amount of Ibrutinib will continue to hold the disease at bay and forestall any proliferation or mutation.

BeckyL USA

[bennevisplace]

I don't see the need to pitch BTK inhibitors against Venetoclax. Their strengths are complementary and the combination seems to work better than either component.

[Smakwater]

Len,

Being a spawn of the V-clax I find this interesting, but not necessarily encouraging.

Guess we wait and see, or as has been said continue "Watch and Wait". Best enjoy the remission Honeymoon until the Furminator gets this worked out.

JM

[lankisterguy Volunteer]

Update today:

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1a. Re: Can Venetoclax/Obinituzimab reduce the risk of additional somatic mutations?

From: Date: Fri, 24 Jul 2020 14:02:42 EDT

Dr. Furman,

Is V/O not as effective in stopping proliferation because the treatment is stopped after a year? Or is V/O just not as good at stopping proliferation?

Thanks,

Mark

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1b. Re: Can Venetoclax/Obinituzimab reduce the risk of additional somatic mutations?

From: Rick Furman

Date: Fri, 24 Jul 2020 14:11:17 EDT

It is more due to the differences in the mechanism of action of venetoclax versus the BTK inhibitors.

Rick Furman

[newyork8 in reply to lankisterguy]

I am currently uMRD bone marrow from Ibr alone. I have been in and out of uMRD bone marrow. last 2 BMB uMRD. To me this means our detection of 1/10000 is not sensitive enough. I want to get the Cloneseq1/100000 MRD test. Also I see no logic in stopping Ibr except for financial reasons as my uMRD did not ensure coming out of uMRD status a few months later. I believe stopping IBR would be an invitation to proliferation. Doc Furman you there? Can I buy you a slice of Rays pizza for lunch and discuss some day when I'm in NYC...lol. (or did lots of Rays pizza on 77th and Lex 50 years ago cause my CLL!) Btw you are a comfort to me and others I'm sure who follow you)

[Canuck901]

Dr Hillman said the combo is somewhat almost curative in some individuals.

Has he some fantastic results , again but not everyone responds the same