2nd Update on Possible Richters Transformation

[ReneeSusan]

The upside is I don’t have RT, but I did pick up some more high risk markers in addition to : 11q and unmutated. I learned in July the results of the DNA sequencing study. I picked up TP53, Notch1, ATM and few other ones that predispose me to head and neck cancer and cognitive decline. They did not find 17p del, thank God! 3 out of 4 high risk markers is more than enough to deal with. I was told I picked up these mutations because I was on Venetoclax. Honestly, I have not read about that, just the mutation that makes you resistant to Ven. Are any that I listed that specific mutation? My doc insists Ibrutinib, but we came to a compromise on Acalabrutinib after I found out I have a minor leaky mitral valve. Lucky me! But I m concerned with these mutations about developing a secondary cancer from the BTK inhibitor. Venetoclax is safer with regards to developing secondary malignancies, but my doc says absolutely not! So, My question is for the physicians and scientists in this group, does Ven cause these mutations or is this the result of an 11year CLL journey that started with unmutated ighv and just progressed over the normal course of time with this disease? I was treated with chemo B&R twice and I think the mutations were from the chemo, but It’s just an assumption. I will be starting Acalabrutinib in a few weeks, trying to put it off as long as possible. Lymph nodes have increased significantly along with fatigue and my counts are higher than anytime since I was diagnosed. Now I’m starting to wonder, if I fail Acalabrutinib also where do I go from here? Chemo is definitely out of the question and so is Gavyza (sp?) because of some other marker I can’t remember. And could Richter's still be lurking out there?

If anyone has some insights to share, it is much appreciated!

Trying to stay positive, but feel like I KO’d by Muhammad Ali.

Renee

[81ue]

That's an interesting issue. I never heard of it. However there are articles about mutations in the gene that encodes the BCL-2 protein targeted by venetoclax. But no info that P53 or ATM mutations are caused by venetoclax.

Here's an article that says "BCL2, which is part of the p53 signaling pathway" cancer.gov/news-events/canc...

[ReneeSusan in reply to 81ue]

Dear 81eu

Thanks for the article. That may explain things, but I would need someone to help me understand it better. I guess the Ven affected the to53 pathway incorrectly? Or something went wrong not causing cell death? Ugh Anyway, it’s no longer an option and I’ll be starting Acalabrutinib pretty soon.

Thank you for sharing your insight.

Renee

[AussieNeil Partner Administrator]

Non chemo drugs like Venetoclax don't work by damaging DNA, but by interfering with cellular pathways. DNA damage that randomly arises during CLL cell division or from chemotherapy treatments, can result in a subclone with that additional damage becoming dominant, if it provides a competitive advantage to that subclone. That's how you can develop Venetoclax resistant CLL.

With regard to the "few other ones that predispose me to head and neck cancer and cognitive decline.", that correlation only applies if you have those DNA markers in your inherited DNA present in all your body cells. If you have picked them up in just your differentiated B-lymphocytes which have become CLL cells (which I expect were the cells tested), those risks are not a concern for you. Cells with that damage would have to be present as differentiated brain and head and neck cells.

For the moment, relax about being cleared with regard to Richters - that must have been scary. Look forward to your life improving on Acalabrutinib!

Neil

[ReneeSusan in reply to AussieNeil]

Dear Aussie, that’s what I read, so I don’t know why they blamed Ven She did not say I picked up the r3istant mutation and from what I read none of the mutations i did get fit the bill, My feeling is she does not want me to have Ven as an option. She consistently pushed Ibrutinib even with all my concerns and fears. No empathy there! The compromise is Acalabrutinib so I am keeping fingers and toes crossed I can tolerate it and that it works!

Thanks for sharing your insight.

Renee

[LovecuresCLL]

Hi Renee Susan,

I wish I knew the answers to important questions that you are posing. You are putting up a brave fight. I am not sure I understand the mechanism of how mutation development over time myself.

I am sorry I am not able to help. Just wanted to say I am still here listening and offering support .

- John

[johnl]

I am not a Dr., but I have never heard of this before from Venetoclax. However, the B in BR is chemo and I think that could cause this. If I were you I'd find a CLL specialist and get a second opinion.

john

[ReneeSusan in reply to johnl]

Thanks john1, believe it or not, I see a CLL specialist at UPENN. Scarey!

Renee

[J_88 in reply to ReneeSusan]

Venetoclax would not cause you to pick up other markers. You would just develop a resistance some do some don't. Ven dosen't cause DNA damage like chemo as Neil said.

[ReneeSusan in reply to johnl]

Dear love cures all

As always you are so kind and caring. I am very grateful to have this forum to rant, get information and support! Thank you.

Renee

[DriedSeaweed]

Maybe we will find out in the coming years if venetoclax does not wipe out the more troublesome clones.

[ReneeSusan in reply to DriedSeaweed]

I guess more time is needed for many of these newer drugs to know their true effectiveness and their drawbacks.

R

[DriedSeaweed in reply to ReneeSusan]

At least these days there are a lot of options in the pipeline. Who knows what could be announced by the end of the month or year.

[PSP52]

You are so strong and knowledgeable. It is good that you have an inquiring mind to challenge your doctor. I wish you the best in getting the Acalabrutinib that you want for your treatment.

Pat

[ReneeSusan in reply to PSP52]

Thanks Pat, I found out how very important it is to educate myself and be my own advocate! And one of the best things I did was to be part of this forum with some very highly educated fellow callers!

Wishing you all the best!

Renee

[rafew]

Hi ReneeSue. Not sure why the Dr. nixed Venetclox unless your lymph node tumor burden is high enough to cause TLS. But you could possibly debulk using Acalabrutinib before starting the Venetclox. Best wishes.

[ReneeSusan in reply to rafew]

I was hoping for that combo, but doc thinks Venetoclax is the cause of the new aggressive markers. I was on Ven for 14 months, went into remission, but had to D/C Ven due to neutropenia and a very poor immune system. So not an option for me now.

Renee

[Smakwater in reply to ReneeSusan]

ReneeSusan,

Forgive that I am not a physician or scientist, but I do play an analytic neurotic in real life.

Neutropenia is a known side affect of venetoclax as is with many CLL treatments, and it is commonly treated with G-CSF. There is currently an arising perspective that venetoclax may have the possibility of discontinuation if an acceptable MRD can be reached, and that bone marrow can possibly recover afterwards.

ascopubs.org/doi/10.1200/JC...

dovepress.com/the-expanding...

Although very rare and probably not the case with you, neutropenia can even occur in CLL progressive disease even before treatment. ncbi.nlm.nih.gov/pmc/articl...

I have red hundreds of accredited publications regarding venetoclax and have not found any evidences of it causing the appearance TP53, Notch1, or ATM. These bad actors would have more than likely shown up prior to any treatment with the proper and accurate lab test. The only proven venetoclax resistant influence that I am aware of is the GLY101 VAL. cancerdiscovery.aacrjournal...

If your doctor can produce such a publication, please forward it. I am very interested to know this. If Venetoclax is clinically known to cause TP53, Notch1, or ATM, I would expect FDA to pull it's recent approval, as the combination constitutes a complex karyotype especially with the 11q and unmutated IGVH.

I am glad that you did not develop RT.

JM

[ReneeSusan in reply to Smakwater]

Thanks JM please see Brian Hoffman’s response to my post. It makes sense and answers the question. The reality is CLL is a smart disease and it finds a way to resist cell death by creating clones. I do think that the mutations, 11q, tp53, ATM, Notch1 is more likely the result of being treated with chemo twice along with the natural course of disease progression over 11 years. I had full diagnostic labs at diagnosis, then in 2017 right before Ven treatment. The only aggressive marker was unmutated ighv. I am grateful it wasn’t RT!

Renee

[Yuck]

Hi Renee,

All that you wrote seems like a confusing mystery, yet you are receiving treatment at a great place. I wish you the very best.

I am wondering about your strategy to delay Acalabrutinib as long as possible. I am also wondering if your Dr. can reassure you that he/she has discussed your case with another CLL specialist, since it seems complex.

Looking forward to reading your positive results with Acalabrutinib. Good luck with it.

Best,

Yuck

[ReneeSusan in reply to Yuck]

Dear Yuck, I have no idea if she has conferred with another specialist and I wish she would. She gets kind of defensive when I ask a lot of questions. She really seemed offended when I told her no to Ibrutinib. Like who was I to question? It’s my body, my journey and if Acalabrutinib has a safer side effect profile, profile why not give it tome? She told me not to online to any forums or support groups because I would only get negative responses abouttreatment side effects, really? She has no clue how informed and highly educated our CLL community is. Very frustrating.

Hope you are doing well. Thanks fir responding,

Renee

[bkoffman CLL CURE Hero]

As others have said, venetoclax doesn't cause DNA damage, but it makes sense that it can put selective pressure on the CLL and allow more resistant or aggressive clones to grow out. With TP53, I would recommend a combo approach. Stay strong. We are all in this together. Brian CLLSociety.org

[ReneeSusan in reply to bkoffman]

Brian thanks for sharing your expertise. It makes sense the way you explained it. My CLL specialist discussed combo but I had a bad reaction to Rituxan and she also said one of my markers from the FISH test makes me less responsive to monoclonal antibody drugs. Hoping Acalabrutinib works cause I don’t think am not a candidate for CAR-T or stem cell transplant.

Renee

[HopeME in reply to ReneeSusan]

Hi Renee:

Why wouldn’t you be a candidate for CAR-T or stem cell transplant? I wish you all the best with Acalabrutinib.

Mark

[ReneeSusan in reply to HopeME]

Age and other health factors, I think. Plus my doc has never discussed these with me.

[HopeME in reply to ReneeSusan]

Hi Renee:

I know you have explored second opinions in the past but based upon your relationship with your current doctor it seems like you should try again. I realize that time, money, work, geography, insurance, etc. can limit options but this is about your life so why not? Further, any two highly qualified CLL doctors can have very different opinions on how to treat the disease given its complexity and the evolving treatment landscape. Thus, it is healthy to get varying perspectives. Finally, if your doctor hasn’t talked about future options such as CAR-T and stem cell transplants even if only to rule them out it would make me uncomfortable. Part of a doctor’s job is to explain not only their immediate approach to your treatment but also their longer term approach to your treatment.

You have been through a lot but you are a fighter so why not fight to get care from someone you better connect with?

Best,

Mark

[ReneeSusan in reply to HopeME]

Dr. Hoffman recommended the free second opinion program expert access at the CLL society. I think that’s a great option and will look into it.

Renee

[bkoffman CLL CURE Hero in reply to ReneeSusan]

If you live in the USA, consider our free second opinion program, expert access ( cllsociety.org/cll-society-... . Notch1 mutations don't respond as well to rituximab or ofatumumab, but as far as I know the jury is out on obinutuzumab.

[ReneeSusan]

I live in New Jersey and will certainly consider. Yes thank you, I couldn’t remember which mutation didn’t respond. I’m busy going to research notch1 and Obinutuzumab and see what my specialist thinks. Thank you.

[Kokobean]

I don’t know a lot about the different drugs and their effect on developing additional markers, but my husband did develop a second deletion before he started treatment. He was on Enbrel and methotrexate for RA though so ? That probably doesn’t help answer your question, but more to ponder.

[ReneeSusan]

Dear Kokobean, yes I agree more to ponder. Has the new mutation made him more resistant treatment?

Renee

[Mystic75]

Hi Renee Susan,

Just want you to know you're in my thoughts - I hope you are able to get the answers you need as soon as possible and wish you a very successful treatment with Acalabrutinib.

This must be very overwhelming for you right now but the good news is it isn't RT. If you can identify what your next treatment would be if you need it after Acalabrutinib, it may give you some peace of mind. I totally understand the worries you are having to deal with.

💖💖💖

Big hug,

D.

[ReneeSusan in reply to Mystic75]

Hi Mystic75. Thanks much for the encouraging words. I won’t know what’s up after Acalabrutinib till I see my doctor in November. Not sure how many options are available to me. Brian Hoffman told me Obinutuzumab could be one that could be combined with Acalabrutinib so we’ll see. The good news is new drugs are being approved every day. Sending hugs back!

Renee

[Mystic75 in reply to ReneeSusan]

❤️

[rafew]

ReneeSusan , I'm pretty much where you were when you wrote this and I'm wondering if you could share how it's been working out for you? My remission from VR was about 10 months before progression began and 14 before I began [yesterday] Acalabrutinib. Best Wishes.