IDH1 and Notch1

[DaveCll]

I was just informed by my doctor that I have a Notch1 and IDH1 mutation. Does anyone else have these mutations and what to do about it?

[SofiaDeo]

There's nothing specific to "do", these newer tests (so people like me a decade into diagnosis didn't get them) may be considered along with other test results, to describe/possibly predict how the CLL variant in people with various test results may behave.

[DaveCll in reply to SofiaDeo]

They also told me the 1DH1 is associated with MDS. I too am into a little over a decade. Originally diagnosed in 2010

[DoriZett]

I have Notch 1 but no one talks about it in regard to altering treatment. My understanding is it is one of the “less desirable “ markers. We can’t do anything to alter. Best to you.

[Skyshark]

23 % of CLLers have Notch 1. Everything was a cause for concern 5-7 years ago when the only treatments were chemo. Just 15% had a "very good" response to FC-R but they have to treat 30% with FC-R to find them.

Now the key markers are IgHV and TP53.

ashpublications.org/blood/a...

IgHV mutated irrespective of TP53 is goodish, about 38-40% have this marker.

IgHV unmutated with TP53 wildtype is not so good, about 50-52% have this marker pairing.

IgHV unmutated with TP53 del/mut is poor, about 10% have this marker pairing. But that "poor" is about as good as it ever got on chemo except for the 15% that did very well on FC-R.

Any report prior to 2015 can be discarded. Any report after 2017 should be studied carefully to make sure the result is for new therapies.

IDH1 appears to be (or was this is a 2016 report for chemo patients) a good marker with better response to treatment.

clinicalepigeneticsjournal....

[Gawee in reply to Skyshark]

Hi Skyshark may I ask if a fish result showing TP53/CEP17 positive is also refered to 17p deletion? Or is this different to 17p deletion? Thanks in advance

[DaveCll in reply to Skyshark]

back in 2010 I Received FC-R but once had little improvement so they changed it to Bendimustine I had four cycles on it and then had a DVT in my leg so they stopped the rest of the treatment. I went into remission for one year. by that time they just approved inbrutinib and it worked great on me. My doctor just told me that due to the FCR and the Bedimustine it caused my cells to now have MDS.

[Skyshark]

17p deletion takes out the TP53 as TP53 is in/on 17p.

I'm confused by positive/negative genetic markers as it's usually wildtype, un/mutated and deleted. There have been discussions about this on healthunlocked before but I don't know if it was resolved.

[AussieNeil Partner Administrator in reply to Skyshark]

This post in the related posts from 6 months ago has the most replies

healthunlocked.com/cllsuppo......

[Skyshark in reply to AussieNeil]

It's not Notch1 that I'm confused by. It's the positive/negative.

Positive/negative can't express the three genetic states of intact, mutated and deleted.

Is +ve/-ve, present/absent = intact/deleted and where is mutated?

Or is +ve/-ve, intact/damaged which lumps all genetic abnormalities together.

Or is +ve/-ve, a simple expression good/bad prognosis?

[Gawee in reply to Skyshark]

Sorry for sending the pic here. We are not sure if this shows 17p deletion.

Fish result

[Skyshark in reply to Gawee]

That's 17p/TP53 deleted, ATM deleted and Trisomy 12.

Seems positive means it exceeds the cut-off threshold.

[AussieNeil Partner Administrator in reply to Skyshark]

Gawee , I've not seen a pathology lab presentation like yours before, but I agree with Skyshack in considering the top table is stating if you are positive or negative for each of the FISH probe tests finding what they are looking for - evidence of damage above the thresholds listed in the bottom table.

These pathology reports are highly condensed medical jargon. So please confirm with your specialist, your understanding that you've gleaned from feedback here and how that influences your CLL management.

Skyshack,

I agree - these reports in general could be more consistently presented. I too take it that positive means that the FISH probe results have reported more damaged/mutated DNA than the relevant threshold. The use of mutated is also confusing. When reporting an IGHV result, you ideally want to see that your CLL DNA in chromosome 14 has somatic changes in the IGHV genetic information to produce a different B cell receptor than what was coded at birth (germline).

Neil

[Gawee in reply to Skyshark]

Thanks for the clarification. was just confused why the display says “TP53/CEP17” instead of “TP53/17p”. I thought CEP17 is different from 17p.

[SofiaDeo in reply to Gawee]

It is, I agree the above posted results are a bit confusing. It's hard to tell if there is actually a deletion or just a mutation/problem at CEP17/possibility of gain at that centromere. I am reading that problems with CEP17 are associated with solid tumors, and a google search is bringing up breast cancers mostly.

I wonder if given the context of other results /diagnosis of CLL, the interpretation should be obvious & we laypeople who aren't experienced at reading these things just don't readily understand.

[Snakeoil]

To answer directly, what you must do with Notch1 mutation is to reject any therapies that include Rituximab, such as FCR.

CLL patients with NOTCH1 mutations do not benefit from rituximab-combining therapies, which may be related to lower levels of CD20 expression in NOTCH1 mutated cases.

pubmed.ncbi.nlm.nih.gov/261...

[Skyshark in reply to Snakeoil]

Did you mean to post the recently posted link to this?

ncbi.nlm.nih.gov/pmc/articl...

Among new CLL genetic lesions, only NOTCH1 mutations behave as a candidate predictive biomarker. Indeed, among CLL harboring NOTCH1 mutations, treatment with FCR, R-Clb, or O-Clb does not result in the expected increase in PFS compared with treatment with FC or with chlorambucil alone.66-68 These observations point to NOTCH1 mutations as a biomarker of resistance to the anti-CD20 monoclonal antibodies rituximab and ofatumumab in CLL. The outcome of CLL patients treated with obinutuzumab combined to chlorambucil is improved independent of NOTCH1 mutation status, suggesting that the augmented cytotoxicity of obinutuzumab or the increased dose of the anti-CD20 antibody used in the obinutuzumab-chlorambucil schema overcomes NOTCH1 mutation–associated resistance to rituximab.67 The mechanism underlying the anti-CD20 refractoriness associated with NOTCH1 mutations remains obscure.

[Snakeoil in reply to Skyshark]

Was not aware of that paper but good that what I said still stands 😊

Fixed link.

[Skyshark in reply to Snakeoil]

The link you posted goes to the Pubmed login page and not a report.