Venetoclax second line treatment failing. (57yrs old)

[spud2212]

Hi all,

I was diagnosed in 2015 with CLL with 17p del & started Idelalisib at the Christie which got it under control for a few years until it failed. I was then put on Venetoclax which amazingly got me into remission but it has now started to fail.

My question is what are the new drugs(combinations etc) & treatments that might help me back into remission?

[Justasheet1]

Spud,

My advice would be to seek out a clinical trial using the only approved drug left, ibrutinib, and something new and not yet approved.

You are young and 17p so you need to make a great decision with a true expert doctor.

Jeff

[spud2212 in reply to Justasheet1]

Thanks Jeff 👍

[lankisterguy Volunteer]

Hi spud2112,

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Ah! a CLL brother!! My treatment sequence: Rituxan 2010, Idelalisib 2012-2015, Ibrutinib 2015, Venetoclax 2016 to current, Acalabrutinib 2022 to current. I will learn if my MRD test shows improvement downward or rapid progression when I get tested next on April 26.

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I am watching for the much anticipated FDA approval of Pirtobrutinib / LOXO 305 onclive.com/view/pirtobruti...

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I am also looking for a clinical trial in BiTE

en.wikipedia.org/wiki/Bi-sp...

amgen.com/stories/2018/08/t...

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but a recent posting by our own Admin Jm954

healthunlocked.com/cllsuppo...

has thrown some doubt in my mind

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I also am looking for a clinical trial for CAR-NK that does not require me to move to Texas.

mdanderson.org/newsroom/cd1...

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And hopeful that the trials in progress on CAR-T will resolve the low success rates in CLL

lls.org/treatment/types-tre...

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Len

[MrMidnight in reply to lankisterguy]

Acalabrutinib after Ibrutinib? Did you have to finish taking Ibrutinib because of reasons other than resistance?

[lankisterguy Volunteer in reply to MrMidnight]

I had an itchy skin rash on Ibrutinib in 2015. We paused the drug for 4 weeks, the rash went away, and immediately after restarting Ibrutinib, it came back.

7 years later and while using weekly phototherapy (lightbox treatments with narrow band UVB rays) for psoriasis, there is almost no rash change with Acalabrutinib.

Len

[MrMidnight in reply to lankisterguy]

Thanks for the explanation.

[cajunjeff]

Spud, I am no expert but I would observe that the sequencing of your treatments thus far has not been typical, at least not to my amateur understanding of how cll drugs are sequenced. To my understanding, Idelalisib is usually used only after btk inhibitors (like ibrutinib and acalabrutinib) and venetoclax have failed. A more typical sequence would be to start on a btk drug, then move to venetoclax if it fails, and then to idelalisib (or a similar inhibitor drug).

This doesn't mean the sequence in which you have taken drugs is wrong, these drugs are all relatively new and they are still trying to figure out the best sequencing and combinations to use. Making it even more complicated is the fact that what treatment sequence is best for me might not be best for you. Cll is a heterogenous disease and treatment plans are not one size fits all.

The good news, I would argue in your case, is that you still have btk drugs in your arsenal, which drugs might get you your longest remission. The odds of you responding to a btk drug are quite high and no one can really say how long it might work for you. Given the choice, I would take acalabrutinib over ibrutinib, but they are both great drugs that work to some extent for almost everyone.

Btk drugs can be combined with monoclonal antibody drugs to make them more effective, but some cll doctors might say a btk alone is all your need.

Beyond btk drugs, there are other possibilities including a different class of btk drugs that can work if covalent binding btk drugs fail. Car T and Car nk are promising treatments, more in the last resort category.

The history of the development of cll drugs tells us the drug we eventually use might be in development now. Bispecific antibodies are a good example of a promising cll treatment in development that might be standard therapy in a few years.

In summary, I would assume your doctor will start you on one of the btk drugs, which is a great arrow to still have left in your quiver. If you have access to a cll specialist, that's the best thing you can do.

[SofiaDeo]

There's been some discussion in the literature of adding a second agent to monotherapy as soon as resistance starts to emerge. I think only clinical trials are doing this, though. And if I am remembering correctly, it is with the BTK inhibitors. It's something to discuss. Many of the newer protocols are recommending at least 2 drugs, to avoid resistance.

[ornstin in reply to SofiaDeo]

I am finding it slightly difficult to understand the logic of adding a second agent to monotherapy as soon as resistance (to the monotherapy) begins to emerge. By that time the mechanisms that have caused the resistance (I believe some form of mutations which develop over time) will be in place, so would a second agent be able to reverse them (seems unlikely)? If not, what would be the point of staying on the first agent?

With regard to your last sentence: I assume the rationale is that a drug combination would hit the CLL harder, which means less time on therapy (good in itself), and therefore less chance for resistance mutations to develop.

I think various trial results have shown that a BTK inhibitor can be more effective when used in a drug combination rather than as monotherapy (although this would of course depend on the exact combination used).

[ornstin]

In addition to what Justasheet1 said, you might be eligible for the CAR-T cell trial which is still recruiting CLL patients. I obviously cannot say whether this would actually be suitable for you-you need to discuss with your specialist.

I think the standard NHS treatments in your case would be Ibrutinib or Acalabrutinib. As you are 17P deleted it is unlikely that FCR or BR would be of much help (I expect you have been told this already). Antony

[LeoPa]

Did they consider adding a Rituximab or Obinutuzumab to it?

[spud2212 in reply to LeoPa]

I think I had 6 infusions of Rituximab when I started the Venetoclax.

[Hoffy]

Combining Imbruvica or other BTK imhibitors ( Acal, Loxo305) with Venetoclax may help for a bit. CAR-T trials maybe a good option to look at as well.

Be well,

Keep us posted,

Hoffy

[Mahere]

Hi Spud, your path sounds very similar to mine. I'm 57 and was diagnosed in 2012. Had FCR in 2014, relapsed then started Venetoclax (trial) in 2017. Venetoclax has failed - my consultant is now looking at either putting me onto Acalabrutinib (or maybe onto a Pirtobrutinib trial that she's running but looks like I'm ineligible for that). I have TP53. She keeps mentioning stem cell transplant as the next option and that scares me so hoping something else comes along before that decision needs to be made!. So short term ... very likely I'll be starting on Acalabrutinib in the next few weeks. Cheers, Ed (in Dublin, Ireland).