Looking for alternatives with BTK C481 resistant CLL

[micg]

Looking for alternatives. I have had 3 prior treatments from FCR to other chemo to Veneclax and Imbrutnib which was working great until my counts went up again. Turns out I have developed a BTK mutation. Been seeking out trials and wanted to try loxo-305 (Pirtobrutinib) but it was all filled up and they changed the study criteria. Been researching other potential drugs where there are trials the work thru the BTK C481 resistance mutation. I am pretty much out of options as my current oncologist says I need to find a trial - he can do nothing for me. I have been to 2 high powered institutions, incurred a lot of expense in travel only be told no openings and both told me I need to search for something else. I finally was accepted on one trial and just after they did my bone marrow I was told I did not have the CD2O needed for success of that drug. Feel like I am out on a limb and no where to go. I am not ready for CART-T for financial reasons. Any suggestions would be helpful. Given I am opt of options dont know why Eli Lilly would not provide me the drug outside of trial - but I guess they can't.

[johnl]

What about a Pi3k inhibitor?

john

[micg in reply to johnl]

Thank you. I have considered but and fearful of the toxicity profile.

[lankisterguy Volunteer in reply to micg]

Hi micg,

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I have had all the drugs you mentioned (except Chemo), and would suggest you try Idelalisib / Zydelig - for me it was a breeze, and in general the toxicity profile is very similar to Ibrutinib. In nearly every case, stopping Zydelig if you have a unbearable side effect will stop the side effect.

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There were some trial issues with Pneumocystis - Lung fungus, but I believe they have figured out to monitor CD-4 T-cell levels

pubmed.ncbi.nlm.nih.gov/280...

and/or using prophylactics liked Bactrim (TMP-SMX) or Atovaquone

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Alternatively you might consider adding Obinutuzumab / Gazyva to your Venetoclax. (I realize you are low in CD-20, but it might work)

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There are numerous CAR-T trials around the USA.

lymphoma.org/newsarchive/as...

Dr. Brian Koffman bkoffman might be able to suggest someone that can help you find one.

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Or even a CAR-NK trial like thisL: mdanderson.org/newsroom/cd1...

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Len

[sllincolorado]

It sounds like you have already done plenty of excellent research and you have lived successfully with CLL for a long time so you probably already know about Ultra V clinical trials (I'm on one and they have a new one that recently started). I am not clear if you need to rule out anything with venetoclax. I think TG therapeutics has/had an arm with Ublituximab and Umbralisib only without V but I am not sure if this is still an option. I think those trials are called Unity. I am not smart enough to understand if the CD20 issue would be a problem.

Did anyone suggest a new btk? I know you show a clinical resistance but just curious if anyone suggested giving zanzabrutinib or acalabrutinib a try. I am the opposite. I did not show a clinical resistance to btk inhibitors but acala stopped working for me anyway. So tests provide good info but sometimes they are only data points and should not rule things out completely.

Have you had the free expert opinion from CLL Society? No traveling and free! Not sure if someone on their team would be more knowledgeable than the top notch places you have already tried:

cllsociety.org/cll-society-...

CLL Society and/or Dr. Brian might have a list of trials that you could review.

Not sure if one of the high powered places you went to was MD Anderson. If not, you might try to figure out if you can communicate with Dr. Wierda. He is not my doctor and I have not received any opinions from him but, based on his interactions with others I know, if I was in a crisis I would contact him.

Let us know what you figure out - I am mrd u but with my markers I know it is important to anticipate future options.

Best

[micg in reply to sllincolorado]

Thanks - i think these two BTK inhibitors you mention follow the same general pathway as Imbrutnib and these would have the same resistance given my BTK C481 resistance mutation . Only BTK inhibitors I know of that are reversible like Loxo-305 and IRQ-531. But I will look into.

[Jm954 Administrator]

Have you or your doctors considered Duvelisib? I realise you have said you're fearful of the toxicity profile but this is meant to be better than Idelasilib.

There is a trial of Duvelisib and Venetoclax for relapsed CLL/SLL

clinicaltrials.gov/ct2/show...

Jackie

[micg in reply to Jm954]

I will look at it, thanks but the trial you show exclusion criteria states that if already on veneclaxta.. i will have to do it an a mono therapy. Thanks

[bennevisplace]

jhoonline.biomedcentral.com... Non covalent BTK inhibitors in clinical trials

[micg in reply to bennevisplace]

Thank you. I know I am venting a bit. Yes, precisely my issue. As i look at this chart. I cant seem to get into the Loxo trial w/ the combination of venclexta i.e.NCT03740529 . Believe me I have been to 3 major centers and they are all full. Loxo is pushing me to their new Loxo trial that is randomized with the alternative of what I don't want as I have lung issues because of as a result of CLL. I have a 50/50 shot of getting LOXO/Venclexta and/or some PK3i which I don't want because I am not a good fit because of the side effect profile and my cll related lung issues. Nor would i waste peoples time and/and take a slot only to pullout if they gave me what i did not want. I do like the IRQ-531 but that is a mono therapy. I have advanced/ aggressive CLL and really need Venclexta too. I know I am being stubborn but what I need is a reversible BTK and Venclexta - period. I have even called merek and eli lilly directly and tried to convince them to let me try as I am out of options. Told them don't put me into a trial - I'll pay for the drug and be on my own. Obviously, they said no but desperate time call for desperate measures. I am not ready for CART T as I have to save $ and I feel it is not yet ready for cll - it will be, maybe CART-NG someday. So, I am stuck and maybe one infection away from disaster. I do appreciate all your responses and hearing me out. I will look at the others in the chart and keep pressing. Thanks.

[Jm954 Administrator in reply to micg]

You are doing an amazing job of advocating for yourself but is your doctor also asking the centres of excellence etc for you too?

[micg in reply to Jm954]

Not sure my Drs (plural) know what to do, to be honest. It's complicated but a lot of therapies rely on certain markers like CD20 and CD19 and my are downgraded. They are following up but the options and criteria for some of these trials are proving to be difficult for me given my cytogenics. Options are limited. That is why I am seeking any word. But some of these responses have been helpful and I am taking advantage and it been appreciated.

[Jm954 Administrator in reply to micg]

Is this any help. I couldn't play it but you might have more luck. The title looks promising re information for you

clinicaloptions.com/oncolog...

[bennevisplace]

I can only wish you a successful quest micg.

[studebaker]

So sorry for the situation you are in micg. I don’t know if your doctor could step in to help you to get some treatment on compassionate basis. I think to leave you to find something on your own makes it much mor stressful and difficult for you.

Is there a possibility to go for help to a different doctor ? You are on Venetoclax and Ibrutinib stopped working. Would they consider adding Rituximab? Some people are on Venetoclax monotherapy, would that be an option for you for now, until there is some trial available to you ?

Please keep posting about your experience as a lot of us coming closer to the same dilemma, I am one of them.

Sending you virtual 🤗

Dana

[micg in reply to studebaker]

Thanks for your response. It appears that my downgraded markers cd20 and cd19 is no longer advantageous for Rituximab to work, nor CART T/MK or the Epcoritamab trial that I was just kicked out of because of my biopsy - which kind of starting this whole thread of mine. From what I understand. BTW all you that are following this thread should follow what is going on w/ @ Epcoritamab.