Imbrutinib resistance

[jenxgen]

Is it better to be mutated or not mutated for Imbrutinib resistance?

[annmcgowan]

Hi I don’t think mutated or unmutated predicts Ibrutinib response either way.

I am on flair trial on Ibrutinib and rituximab 6 months in and doing well. I am borderline and have not been told that my IVGH status predicts my response to ibrutinib.

Ann

[Cllcanada Top Poster CURE Hero]

IGHV mutation isn't linked to Imbruvica (ibrutinib) resistance which occurs in another gene... BTK(C481S) and/or PLCG2 to be specific, but there may be other kinases...

~chris

[jenxgen in reply to Cllcanada]

Let me clarify by saying is it best to be BKT(481S) mutated or non mutated?

[cajunjeff in reply to jenxgen]

I am no expert but I think the btk mutation predicts ibrutinib resistance, so being btk not mutated would be better.

[Cllcanada Top Poster CURE Hero in reply to jenxgen]

unmutated... this is totally different than CLL mutated or unmutated you hear about, don't confuse the two...

medscape.com/viewarticle/89...

[gardening-girl]

jenxgen, I'm still not exactly certain exactly what you are asking. There are two major pathways to ibrutinib resistance. If resistance to Ibrutinib is caused by a C481S mutation (that is the amino acid cysteine is replaced by serine) ibrutinib can no longer bind covalently to the BTK enzyme, inhibiting it for the life of the protein. However, ibrutinib can still bind non-covalently and inhibit BTK, but just not for the life of the protein. That is the rationale for continuing ibrutinib treatment (sometimes at higher doses) while adding venetoclax.

Other BTK inhibitors that work with C481S mutations are being developed for example Vecabrutinib (SNS-062):

ir.sunesis.com/news-release...

The second major pathway leading to ibrutinib resistance are mutations in the PLCg2 gene causing a gain-of-function that occurs in the protein immediately down stream of BTK essentially bypassing the need for an active BTK.

Both resistance cases are caused by mutations, but only the first is a mutation in the BTK gene. Patients with either form of resistance can be successfully treated with several alternative therapies. I have seen no data indicating that survival differs depending on the mechanism of resistance.

Please continue to ask, if this did not address your question.

gardening-girl

[Cllcanada Top Poster CURE Hero in reply to gardening-girl]

The OP is confusing IGHV mutation, with Imbruvica (ibrutinib) mutation which causes resistance... apples and bananas.

~chris

[Hoffy]

In general it’s better to be mutated then unmutated.

It sounds strange but the mutated cells are more mature than the unmutated which can be more wild from analogy standpoint .

Be well ,

Hoffy

[Teegolf47]

Gardening-girl has written a very complete and concise description of the genetic mutations that may develop after taking Ibrutinib. I would add that the data shows that the development of the mutations is much more common in patients that have taken Ibrutinib as their second or third line treatment. Patients using Ibrutinib as a front line treatment seem to have less mutational changes.

Also, there seems to be no difference in results between patients having 'mutated' or 'unmutated' IGHV, which as Chris points out is different that the mutational changes that happen after you take Ibrutinib.

Gardening-Girl also mentions ways that this resistance is being addressed and I am currently in an Investigator Initiated trial at UCSD in California where they are testing the theory of both adding Venetoclax, and increasing the dose of Ibrubtinib up to 840mg. After 12 weeks, I am in CR, which I never got after 4 1/2 years on Ibrutinib alone.

Terry

[Yvbb in reply to Teegolf47]

Congratulations on your cr, Terry! I am puzzled by your info that your dosis of Ibrutinib is increased up to 840 mg...or is that with the Venetoclax included?

I am on 420 mg Ib and 400 mg Vtclx. In a discussion recently I learned that it could very well be that the dosis is too high for many patients. I am very curious what all the trial data will learn us.

Wish you good care.

Yvonne

[Teegolf47 in reply to Yvbb]

The dose increase rational is that more Ibrutinib may get rid of the mutation since Ibrutinib at the 420mg dose seems to become less effective. In the original Clinical Trials for Ibrutinib the phase 1 studies took the dose all the way up to a gram (1000mg), and it was shown to be tolerated with the same side effects as with a lower dose, but did not increase its effectiveness, hence the 420mg dose was chosen as the approved dose.

In my trial there are 4 cohorts of 3 patients each, with each new group of 3 patients receiving an increased dose of Ibrutinib. All patients receive the 400mg of Venetoclax. I am the first person and in the first cohort in the trial, so my Ibrutinib dose is 420mg, the same as it has been for 4 1/2 years. My personal view is that adding the Venetoclax creates another variable making it difficult to determine if an increased dose is the reason for success. Another issue is that with my disease burden now so low, it may be impossible to test for the C481S mutation to see if it is gone. I will have a bone marrow biopsy in November to test the depth of the remission to see if I have reached MRD-.

Many patients move to a lower dose of Ibrutinib because of side effects. The most important part of taking Ibrutinib is adherence, making sure you take it daily, whatever the dose. There is also some thinking that once you reach a low disease burden that you may be able to reduce the dose, but that hasn't been tested yet in a Trial.

Terry