The current status and challenges of CAR-T therapy in CLL

[Jm954]

A few members of this group are scheduled for CAR-T and others might find themselves in the same situation in the future so I thought this would be of interest.

"In recent years, novel immunotherapies, including CAR-T cell therapy, have greatly improved treatment options for patients with hematological malignancies. Although CAR-T cells have demonstrated remarkable success in several diseases, including multiple myeloma, acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL), there has been less success with these agents in patients with chronic lymphocytic leukemia (CLL)."

It's a Podcast, so like listening to a radio programme and only approx 10 minutes long. The link is dated March 2023 and is here:

vjhemonc.com/podcast/the-cu...

Jackie

[mrsjsmith]

Thank you Jackie.

Colette

[Sushibruno]

I’m just hoping they will be able to “crack the code”on why it hasn’t been as successful on cll as it is for other hematological malignancies.

[db601]

Thank you, Jackie. I became familiar with this excellent resource this past year. Anthony Mato contributed an update. Marco Ruella’s work in Multiple Myeloma - mentioned in the podcasts - has been with my HemOnc- Adam D Cohen. I know a patient who was preparing for CAR-T at Penn with this group.

?Would there be maximum success if the standard of practice allowed the treatment to be used before the patient sees it as a last resort? (Brittle bones and multiple breaks - become the point at which CAR-T is suggested)

NGS is now being done - mostly on peripheral blood rather than BMB.

? Is there a good reason to prefer BMB rather than the less expensive peripheral blood draw to gain the most knowledge for risk management?

Thank you for any insight you may offer.

Diana

[Jm954 Administrator in reply to db601]

People are often reported as having no detectable CLL in the blood but CLL is detected in the bone marrow, so bone marrow is a more reliable indicator of the true picture.

[Oleboyredw-uk]

Thanks for sharing Jackie. I listened to the first two parts as I am, obviously, very interested. I noticed both speakers talked about Liso-cel specifically. I had Obe-cel, developed by UCLH, one of their design changes was to have a fast-off to help with the t-cell exhaustion issue. Bottom line, it's good to know there are multiple development threads.

I have a personal opinion on use of BMBs. It seems to me that there is an indirect relationship between peripheral blood numbers and state of bone marrow infiltration. So, given that I guess a BMB will be more accurate than making an assumption based on peripheral numbers. On that basis I am happy to have BMBs. In fact signing up for the trial I am on I committed to having nine BMBs, seven of which have been done. No medical training so happy to be proven wrong, just my opinion.

Best to all, rob

[ErieSailor in reply to Oleboyredw-uk]

how painful are those BMBs? That’s one thing that worries me about participating in clinical trial!

[SofiaDeo in reply to ErieSailor]

IMO it's the skill of the person doing it, as well as if your marrow is cooperating, that determines *if* you have pain. I've had virtually painless ones from experienced folk. I had one notable exception when they took me late so my premeds had worn off, and the medical residents doing it (not experienced staff) took multiple attempts at a sample.

These are experienced trial people. The only time on a trial I had any major discomfort (for me it was more nausea from the pressure as opposed to actual pain, plus my entire body broke out in a sweat all over which was upsetting) was when my marrow kept crumbling, and it took several tries to get a good sample. But I had no lasting bone pain from bruising. Trial nurses and docs have done a number of them, before they get to be trial nurses and docs.

[Oleboyredw-uk in reply to ErieSailor]

They were OK. I think over the past ten years I've had a further six. Only one operator I'd not want again. I turn down the option of gas and only go with local anaesthetic because they won't let you drive home after having gas. The local is administrated by same person a few minutes before the procedure.

I assumed it was my pain you were asking about. In discussion with one of the operators I discovered after a few their had normally starts to ache.

It is definitely down to the skill of the person doing the procedure.

Best, rob

[db601]

BMBs - I think - more accurate - are getting harder to get. In Interventional Radiation the procedure is pain free but more expensive. It has become another challenge to get the test and feel complete surveillance is being done.

Jackie, With CAR-T is the follow up - post procedure - testing / complicated?

Rob- good luck w the clinical trial!

Diana

[DanBro1]

Informative podcast. Sad to hear Car-T doesn't work well against CLL because CLL really does a job on our immune system T-cells. I sort of got the impression that current treatments for CLL are satisfactory (Ibrutinib and Venclexta) and maybe newer drugs aren't that necessary.....

[SofiaDeo in reply to DanBro1]

Nah, the more choices the better. Not everyone responds to the main ones. If ibrutinib was the only BTK choice, I would never be able to use a BTK, I reacted really badly to it. I'm in a minority, and I am glad for options. There are a few here posting that pirto has been a godsend, and others happy that zanu came along. And if there were a choice of BCL2 agents, perhaps others here wouldn't *need* to stay on V and deal with extra G-CSF and/or Epogen injections.

[Peggy4]

Thank you Jackie.

Peggy

[bennevisplace]

Cancer immunotherapy is such a fascinating area of research. Per DanBro1 healthunlocked.com/cllsuppo... it seems that CLL is in danger of getting left behind in the CAR-T stakes.

Pre-treatment with a BTK inhibitor was mentioned in the podcast (and elsewhere) as a way of reactivating exhausted T-cells prior to harvesting, although I believe the reactivation process has yet to be fully described. I have read at least one paper claiming that Ibrutinib, but not Acalabrutinib, does the job (implying that different off-target effects are involved). The podcast mentions the use of both BTKi s as well as Zanubrutinib in different CAR-T trials. I have also read that pre- and concurrent treatment with a PI3K inhibitor improves the CAR-T ashpublications.org/blood/a...

This is a pretty good written summary of the present state of CAR T therapy for CLL hematologyandoncology.net/a...

[bennevisplace]

It's worth referring back to the Update on CAR-T and CAR-NK therapies posted by CLLerinOz a couple of months ago, which included reference to a paper on CAR-NK therapy in CLL healthunlocked.com/cllsuppo...