CAR T was just approved for Relapsed/Refractory CLL/SLL ( Potentially 20% CURE rate)

[bagelstreet225]

What are your thoughts/suggestions/comments?

Thank you,

Pat

onclive.com/view/dr-kenderi...

[cajunjeff]

Hello bagelstreet. It’s great news they are making progress with CarT for cll. With all the progress being made with cll and the novel therapies, there remains a big unmet need. What do we do if our Cll becomes resistant to btk drugs (like ibrutinib) AND to bcl drugs(like venetoclax)?

Car T is one option, but even with these encouraging results, there are way too many people who either dont have access to Car T, or dont do as well on it as others. They keep improving CarT, which is good. The response rate of 45% needs to get better, that leaves too many of us running out of options.

The recent history of cll has been encouraging. Lots of people were running out of options when ibrutinib came along. Lots of people were running out of options when venetoclax came along.

Fortunately for us, Car T is but one therapy trying to occupy that “what to do after ibrutinib and venetoclax stop working” place. We haven’t seen the home run drugs like btk and bcl drugs emerge yet, we just have to keep the faith one will. I dont know if it will be Car T, bispecific drugs, non covalent btk drugs or something else. Fortunately for us, there are lots of contenders in various clinical trial stages.

It’s a process and it’s good to read that Car T might cure some of us or put us in longer remissions. We still need some therapy to emerge with a better response rate. I think that will happen, but Im sad to say it might not be in time for some of us. I think a therapy will emerge and it’s certainly encouraging to read that progress is being made with Car T. I am on a btk drug now and I guess at some point I might need Car T. Like many, I just hope the cll treatment technology and new options stays a step ahead of my cll.

I’m optimistic our options will continue to evolve.

[bagelstreet225 in reply to cajunjeff]

Thank you for your input/feedback. I remain optimistic. There is no other choice. I think it's NOT a matter of if we'll have a cure but when. Some clinicians are more conservative than others. That's fine. According to Carl June, the pioneer of CAR T at the university of Pennsylvania, it's a CURE. According to Peter Hillman, university of Leeds (UK), we are moving closer to eradicating CLL. He talks about the FLAIR study. More than 80% of the trial participants achieved UMRD (undetected minimal disease), which is extordinary. Yes, it's NOT a cure but can we at least consider a potential functional CURE? Perhaps we're already there. Hillman is also very optimistic. Nicole LaManna, MD, Columbia University, a CLL ROCK STAR, is also very optimistic. Again, it's NOT a question about if we'll have a cure but when. The operative word is when and that "when" is much sooner than we think. What are your thoughts?

[cajunjeff in reply to bagelstreet225]

Well I am as glass half full as there is, but I think for too many of us Cll remains a very challenging disease. I do think some sort of cure of cll is inevitable, the “when” you say will be too late for some, just keeping it real.

And even then, “cure” may not be enough. We have to find ways to restore our immune systems. It doesnt help much if our cll is cured, but we succumb to some illness our depleted immune system can’t fight.

You had asked in your original post for comments and thoughts on the Car t front. . It’s great news for those in early stage cll, car T is getting better. I just think we still need a therapy to emerge with a much better response percentage. I worry about the 55% in the study who didn’t receive a response.

So in summary, it’s great news progress with Car T is being made. But we still need better options that work for more people who are in a challenging places with their cll.

[bagelstreet225 in reply to cajunjeff]

I just began my journey, Jeff. May I call you Jeff? You raise excellent points. If CLL is cured, it's not enough. You know, I've probably had CLL/SLL ( I have SLL) more than ten years, the hem/onc said, I'm a patient at NYU Langone Health. My counts, especially hemoglobin, was also a little low, always and the family quack said, "eat more red meat," or this is "normal" for you, but he never tested for CLL or refer me to a hematologist. NO. My CLL was an incidental finding, had( and continue to this day) no symptoms. To date, my counts are normal, FISH is normal, NO 17P deletion, CD38 negative, Normal Iron, Normal LDH, Normal Coombs. Anyway, that's my story. I have the illness but it's not effecting me. I continue to live my life, eat, work, and remain laser focused on a CURE. CLL will be cured in my timeline, NYU said. I have to know and trust that.

[RogerPinner in reply to cajunjeff]

Jeff, a very thoughtful couple of posts, which I found particularly relevant. I turned down a Car T trial earlier this year. I've exhausted ibrutinib and venetoclax (now in a holding pattern on idelisib....remember him!). When that stops being effective, which I'm sure will be anytime soon, I'm hoping will be approved for one of the non covalent drug trials, hopefully Nurix 5948. Meanwhile I feel well.

Why did I decide against Car T? Obviously the facts you and Bagelstreet pointed out... uncertain success rate for CLL principally, but also I'm 79 and Car T is no walk in the park. Life is full of risks and at my age I chose quality over quantity. Who knows what is right, and I'll never know , unless of course I end up in one of Bagelstreet's alternative universes!!!

Thanks for you many thoughtful and helpful posts over the years.

Roger

[bagelstreet225 in reply to RogerPinner]

Hi Roger,

We respect your decision.

God Bless You

[cajunjeff in reply to RogerPinner]

Roger, very well said. I think whether we have cll or not, something will get us at some point. But for those of us who die suddenly (fortunately or not), we will all eventually have to make some “is the cure worth the pain” decision, at somer point. I honestly don’t worry about it much, the time will come whether I worry or not, so why worry (Alfred E Neumann?). Lol.

I hope I did not come off as pouring cold water on the positive carT news. I was just observing that car T for cll is in its infant stages and while there is great room for hope for car T, its a hard therapy and the harshness of the therapy has to be balanced with the not optimal response rate to CarT.

I’m more hopeful that we can cobble a few years here and there with the non covalent btk and such meds, until the next blockbuster cll drug emerges. I think the advances in cancer therapies the last few years have been exponential as opposed to linear, and that curve will only get better for us.

I honestly dont worry about it much. What will be will be. But I do think you and I will have other options in the near years to come, a further evolved carT among them.

[RogerPinner in reply to cajunjeff]

Jeff, a very rational and philosophical view of our situation, the current one at least. Of course things will get better and new more effective long term treatments will be invented, although whether they will all be affordable (particularly here in the UK) is another question.

In the meantime I'm not complaining. I regard myself as being very lucky to have had a few year's benefit out of ibrutinib and venetoclax, 5 years earlier in my CLL and I would probably have missed out. In the meantime I'll take Alfred Neumann's advice.

Roger

[Sushibruno in reply to bagelstreet225]

I like your optimism.

[bagelstreet225 in reply to Sushibruno]

Thank you. That's appreciated. You know, there are an infinite number of realties. I choose the one without illness. Kindly let me know what you think of the following passage: The concept of countless realities existing beyond our perception is a fascinating one. While it’s rooted in both scientific theories and philosophical ponderings, let’s explore this idea:

Quantum Mechanics and Multiverse Theory:

In the realm of quantum mechanics, particles exhibit probabilistic behavior. The famous double-slit experiment demonstrates that particles can exist in multiple states simultaneously until observed.

The Many-Worlds Interpretation suggests that every quantum event spawns multiple parallel universes. Each choice or outcome creates a branching reality, leading to an infinite web of alternate worlds.

Imagine countless versions of ourselves making different decisions, leading to divergent paths.

Energy Fields and Vibrations:

Ancient spiritual traditions and modern metaphysics propose that everything is interconnected through energy fields. These fields resonate at different frequencies.

Some believe that by aligning our consciousness with specific energy frequencies, we can access alternate dimensions or realities.

Meditation, intention, and practices like quantum jumping aim to tap into these fields.

String Theory and Extra Dimensions:

String theory, a candidate for a unified theory of physics, posits that fundamental particles are tiny vibrating strings. These vibrations occur in higher-dimensional spaces beyond our usual three dimensions.

These extra dimensions might be compactified or hidden from our perception. Could they harbor other realities?

Consciousness and Perception:

Our perception shapes our reality. What we observe becomes our truth.

If there are hidden dimensions or alternate realities, perhaps our consciousness limits our awareness.

Some argue that altered states (through meditation, psychedelics, or near-death experiences) allow glimpses into other realms.

Science Fiction and Imagination:

Science fiction often explores parallel universes, alternate realities, and cosmic energy.

Authors like Philip K. Dick, Isaac Asimov, and Ursula K. Le Guin have woven intricate narratives around these concepts.

Our imagination fuels our curiosity about the unknown.

In the end, whether these realities exist or remain forever elusive, the wonder of exploration drives us forward. Perhaps, just beyond our senses, countless realms await our discovery. 🌌✨

[RogerPinner in reply to bagelstreet225]

Pat, you asked for thoughts on your "scientific theories and philosophical ponderings".

I have been a member of both a Science group (10 years) and a Philosophy group (14 years), so as you can imagine we've discussed just about everything you mention in you post in some depth (maybe not the science fiction so much). As Richard Feynman is quoted as saying “If you think you understand quantum mechanics, you don’t understand quantum mechanics”, which I don't, and that then equally applies to the incomprehensible multiverse idea . Metaphysics I discounted in favour of real physics one year into the philosophy group, which is probably why I joined a science group. String theory...we'll have to wait and see. I'm unclear as to why General Relativity and QM have to follow the same rules. Consciousness is a stable issue for discussion in all philosophy groups, the mind, the brain, etc. The only physical organ in this discussion is the brain, so the rest (I think) have to be functions of the brain and its incredible neural network, One day neurologists will explain it all,,,maybe.

I love your conclusions. "Our imagination fuels our curiosity about the unknown. In the end, whether these realities exist or remain forever elusive, the wonder of exploration drives us forward. Perhaps, just beyond our senses, countless realms await our discovery." I agree with you , except perhaps for the word "just".

Very interesting,

Roger

PS I replied separately to Cajunjeff (as follows) on or original topic of Car T therapy.

[bagelstreet225 in reply to RogerPinner]

Thank you.

[AussieNeil Partner Administrator]

Here's a link to this previous post about the FDA granting accelerated approval of Breyanzi ® (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy: CAR-T healthunlocked.com/cllsuppo...

Neil

[spi3 in reply to AussieNeil]

Ty for,sharing

[bagelstreet225]

Thanks, Neil. Big news.

[johnliston]

I'd like to know what the CLL characteristics are in the patients that achieved CRs. Were they all just mutated 13q like FCR 20 yrs ago or were there some with unfavorable characteristics?

john

[rafew]

CarT has been on my mind for some time. I've had a number of treatments, all have ended with very short or no remission, including Venetclox. [Currently on Acalabruitnib] There are a trials using combinations of BCL and BTK - but that seems to me salvage approach cocktail. So the thought of where do we go when Acalabruitnib stops. Guess we'll face that when we have to. Best.

[bagelstreet225]

There are hundreds of active trials. To the best of my knowledge, they're testing bispecific monoclonal antibodies, BTK degraders and more potent and effective BTK inhibitors. Plus, they're testing combination (BTK and BCL2) therapies. I call it the "one two punch." The following bispecfic antibodies are in clinical trials: Golimumab, Lunsumio and others. Lunsumio was FDA approved for follicular lymphoma. BGB-11417 is also known by another name: Sonrotoclax. This novel BCL-2 inhibitor shows remarkable potency and selectivity, making it a promising addition to the field of cancer treatment. Researchers are closely monitoring its progress, and ongoing studies will provide further insights into its efficacy and safety profile.

BGB-11417 is remarkably potent, with more than 10-fold greater potency in biochemical assays compared to venetoclax, another BCL-2 inhibitor.

Combination of ibrutinib and venetoclax has shown remarkable results in treating chronic lymphocytic leukemia (CLL)

Frontline Treatment:

In a phase II trial, patients with previously untreated CLL received ibrutinib (420 mg daily for 3 cycles) followed by the addition of venetoclax (with weekly dose escalation to 400 mg daily).

The combined therapy was administered for 24 cycles (each cycle lasting 28 days).

After 12 cycles of the combination, 56% of patients achieved bone marrow undetectable minimal residual disease (U-MRD) remission.

Additionally, 30% of patients were bone marrow MRD-positive (with low MRD+ in 19 cases and high MRD+ in 5 cases).

The treatment duration and response assessment were crucial factors in achieving these outcomes1.

Relapse Phase:

After 24 cycles of the combination, 66% of patients achieved bone marrow U-MRD remission.

Among those, 17% remained bone marrow MRD-positive (with low MRD+ in 13 cases and high MRD+ in 1 case).

Overall, 75% of patients achieved bone marrow U-MRD as the best response2.

These results demonstrate the effectiveness of this combination therapy, especially in achieving deep remissions and undetectable minimal residual disease. It’s a promising approach for both frontline and relapsed CLL treatment.