End of the road for PBS-available treaments for me.

[Jotame]

Hi. I live in Adelaide, Australia and I'm anxious about possible treatments now. I was diagnosed at the end of 2016. Starting in 2019 I've had FCR, Nov 2022 splenomegaly and other leukemia symptoms so January 2023 I started on Ibrutinib, giving partial remission but with colitis side effects. Sept 2023 Zanbrutinib but with even worse colitis (diarrhrea). I chose to go back to Ibrutinib. Leukemia symptoms worsened - splenomagaly, febrile episodes, malaise etc. Fourth line of treatment Venetoclax and Rituximab. 6 rounds of Rituximab commenced Feb 2024, and Venetoclax commenced April 24. Between rounds 5 and 6 of Rituximab there was a gap of 6 weeks instead of the usual 4, (due to travel) and the blood tests then showed that all the blood cells counts had fallen dramatically. My haematologist said this indicated that Venetoclax had also failed. And that there were no more government supported (PBS) medications available. He said he was hopeful of a me joining a trial and threw a medication name at me which I didn't record.. I was jet-lagged and exhausted and struggling to catch on to the implications at that appointment, so this is the entirety of my current understanding. Blood tests and phone consults now 2-weekly. My question would be - especially to people who know the Australian protocols - what options might I ask for or be given?

[SofiaDeo]

I am sorry to hear you are having problems, but please review what your doctor has said. The "all cell counts have dropped" and "this means Venetoclax has failed" do not make sense. It's more usual, if one is having too much immune suppression from Venetoclax, such that cell lines are dangerously low, the dose is held until counts return to normal then re-started at a lower dose. This is what the package insert says. So if this were me, I would be asking why I am not a candidate to restart at a lower dose after things normalized a bit.

Others here in Australia will know how to clarify/move forward with what you have been told. But meanwhile, please try not to panic.

[AussieNeil Partner Administrator]

I hope that one of these trials which I've selected from these 17 Australian recruiting clinical trials turns out to be suitable for you: clinicaltrials.gov/search?l...

You usually need to page down through the locations to find where the Australian studies are being done.

RAH and Flinders Medical are sites for "A Phase 1a/1b Open-Label Dose Escalation and Expansion Study of Bcl-2 Inhibitor BGB-11417 in Patients With Mature B-Cell Malignancies"

clinicaltrials.gov/study/NC...

An Open-Label, Multicenter, Phase 2 Study of Iopofosine I 131 (CLR 131) in Patients With Relapsed or Refractory (R/R) Select B-Cell Malignancies (CLOVER-1) and Expansion Cohort in Patients With Waldenstrom Macroglobulinemia (CLOVER-WaM)

Cellectar Biosciences, Adelaide

There's NKX019, Intravenous Allogeneic Chimeric Antigen Receptor Natural Killer Cells (CAR NK), in Adults With B-cell Cancers

It's Phase 1 study at the Peter Mac in Melbourne

clinicaltrials.gov/study/NC...

Another in Victoria

A Phase 1/2, Open-Label, Dose-Escalation and -Expansion Study of the Bruton Tyrosine Kinase Targeted Protein Degrader BGB-16673 in Patients With B-Cell Malignancies

clinicaltrials.gov/study/NC...

Then there's a clinical trial of Lisaftoclax's APG-2575, an experimental BCL-2 inhibitor withe trial sites in Brisbane and Melbourne.

clinicaltrials.gov/study/NC...

cllsociety.org/2023/06/lisa...

A Phase 3 Open-Label, Randomized Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN-CLL-314)

clinicaltrials.gov/study/NC... at St Albans Victoria

I've knocked out some trials that include drugs you've previously had, but perhaps those trials also need to be considered. There's been a huge recent improvement in trial availability in Australia, but I can appreciate your concerns given your past history. Perhaps the Pirtobrutinib as a bridge to the CAR-NK trial is worth checking out with your specialist?

Please keep us informed.

Neil

[Jotame in reply to AussieNeil]

I had an idea the medication started with P. So pirtobrutinib maybe the one he mentioned on the day. Thanks so much for your reply.

[TruthJunkie in reply to AussieNeil]

Neil, You are so thorough in your responses, they give me (and so many others, I’m sure), faith each day. Mahalo nui loa (warm aloha) to you, for all that you do for us here. Suzanne

[scryer99 in reply to AussieNeil]

I was going to suggest BGB-11417 trials, which have several arms running in Australia. It’s somewhat similar to venetoclax but much stronger. Preliminary trial results have been quite good and it recently entered Phase III.

[AussieNeil Partner Administrator in reply to scryer99]

BGB-11417 is available at two sites in Adelaide, Flinders and the RAH.

clinicaltrials.gov/study/NC...

Good catch, strange how I missed it.

Neil

[scryer99 in reply to AussieNeil]

You didn’t miss it; the Phase I is in your list. I have not dug into the Phase III and the Phase I expansion trials but BGB has done a lot in Australia and I would guess the newer trials are available there as well.

[AussieNeil Partner Administrator in reply to scryer99]

BGB-11417 got its start due to Dr Con Tam's efforts in Australia assisting BeiGene. I remember I initially dropped it from my list because it was a riskier phase 1/2 trial. It also may no longer be recruiting.

Neil

[CoachVera55]

Wow so sorry to hear this. I immediately feel panicked too. I know that I can not think in that state so please calm down. Your doctor sounds like a jerk btw & many have in my experience too because of the complexity of your present situation.

Do you have a CLL Specialist & if not please get one. Get clear written laboratory information on the specifics & find a trial. #GODSPEED🙏🏾🙏🏾🙏🏾

Also what SofiaDeo & AussieNeil said…

[Jotame in reply to CoachVera55]

Thank you. I'm sorry to give you a wrong impression of my doc. He's fine. I was just trying to explain in brief terms.

[seelel]

Are you receiving treatment at the RAH or Flinders? (I live in Adelaide).

[Jotame in reply to seelel]

Flinders in the private system

[Skyshark]

I think you should take the advice of SofiaDeo and CoachVera55 .

I would think that the key blood count that indicates failure of Venetoclax based treatment is increasing ALC.

Deceasing in red cell count indicates marrow failure due to heavy infiltration.

Platelets require transfusion. Neutrophils G-CSF. Or a short break and restart.

[Jotame in reply to Skyshark]

please clarify your second sentence; what is 'increasing ALC'?

[AussieNeil Partner Administrator in reply to Jotame]

CLL cells (B lymphocytes), are included in your Absolute Lymphocyte Count (ALC), the total count of all your B and T lymphocytes, one category of the 5 different types of white blood cells (WBCs) that make up your total WBC. So when you said "the blood tests then showed that all the blood cells counts had fallen dramatically", that implies that venetoclax is still successfully killing off CLL cells and something else is responsible for your other blood counts falling, such as your bone marrow not tolerating the full dose of venetoclax.

Given you are having two weekly blood tests and check-ups and that Flinders University/Medical Centre* is one of Australia's CLL centres of excellence I assume your CLL specialist hasn't errered in saying that your venetoclax is failing - I presumed you meant all blood counts other than your lymphocyte counts.

*Flinders is where CLL researchers determined that CLL cells derive their energy from lipids (fats), not glucose, per this post. healthunlocked.com/cllsuppo...

Neil

[LeoPa in reply to AussieNeil]

Does that mean that all lymphocytes derive their energy from lipids, or are monoclonal B cells somehow different in this respect? When I asked AI, I got this reply:

"The preferred energy source of lymphocytes, a type of white blood cell, is glucose. Lymphocytes primarily rely on glucose metabolism to generate energy for their functions, including immune responses. Glucose is a crucial source of energy for various cells in the body, and lymphocytes are no exception. This reliance on glucose helps support the rapid proliferation and functions of lymphocytes during immune responses."

But it gave no links to the source of the claim. I find the RELIANCE ON GLUCOSE/RAPID PROLIFERATION part interesting

Further:

"Lymphocytes primarily rely on glucose as their main energy source. While lipids can also serve as an energy source for cells, lymphocytes are not as efficient in utilizing lipids for energy production compared to glucose.

Here are some points to consider regarding lymphocytes and lipids as an energy source:

Glucose Preference: Lymphocytes have a preference for utilizing glucose as their primary energy source due to the high energy demands associated with their functions, especially during immune responses.

Limited Lipid Utilization: Lymphocytes do have the capability to use lipids as an energy source, but they are more geared towards utilizing glucose efficiently.

Glucose Metabolism: Glucose metabolism provides a rapid and efficient way for lymphocytes to generate the energy needed for their functions, including proliferation and immune responses.

In summary, while lymphocytes can use lipids for energy, they predominantly rely on glucose as their preferred energy source due to its efficiency in meeting their high energy demands."

[Jotame in reply to LeoPa]

Thank you for this reply Neil. As I engage with the forum I'm always struck how constant and dedicated you administrators are, and I'm sure this is what make the forum so active and sucsessful. My deep thanks to you. I find your comment about Flinders being a CLL centre of excellence really encouraging and I'm currently wondering if I should move into the public system as suggested by GSHG.

[GSHG]

Hi Jotame. Dont know what the situation is in SA but have you thought about trying the public health system. Initially we were private but have found our options and access has been so much greater being a public patient at Peter Mac. Good luck

[Jotame in reply to GSHG]

Thanks GSHG. This is really food for thought...private vs public...and one I have pondered previously. I really appreciate you thought. I'm a bit in awe of the Peter Mac and wish was close. My son-in-law is currently being treated there for lymphoma and the pair jokingly call it " the Cancer Guggenheim".

[spi3]

I hope your Dr is a CLL Expert and is familiar with the latest research and treatments - May I suggest that you get a second opinion- rationale- my hubby's 1st CLL Expert (who we loved) referred us to a well known CLL Dr and it was discovered that the original test assessment/diagnosis was horriblely wrong - - so please consider this too. You will be in my prayers so that you get the right treatment too.

[Jotame in reply to spi3]

good thinking but always awkward?

[spi3 in reply to Jotame]

Not awkward because your current Dr will definitely understand it. In many areas of our lives we ask for 2nd options (without even thinking about it) - "how does this look" or "wonder if this car is good on gas" etc

[Silvafoxe]

Sorry to hear you are experiencing so many turnovers. Hope that you will find something that works for you. Sending prayers for you.

[skipro]

It must be stressful and scary to have had so many set backs

I wonder if you could post the lab results you have had to help the community understand best how to help you

skipro

[Jotame in reply to skipro]

Hi skipro, thanks for your care and concern - it really heartening. I've just had 2 nights in the public hospital for IV antibiotics for a sinus infection, so I've seen my haematologist. I'm off venetoclax (which reduces lymohcytes)at least while I'm fighting the infection. I'll have a BMB with results on Aug 16. He wants to review the diagnosis as none of the treatments have had much success. Some numbers for you. 8 July lymphocyte 0.53 30 July lymphocytes 0.39 . neutrophils 0.51 neutrophils 0.24 . haemoglobin 138 haem 77 . platelets 185 plat 83

Waiting with the big unkown is always hard.

Many thanks, Jo

[skipro in reply to Jotame]

Off hand it sounds like the infection has depleted your available marrow and blood cell making capacity

Venclexta may be contributing. How long have you been on it? Might be time for a dose reduction or pause.

Any reasons you're bleeding into your GI tract? Do you have any dark colored stool ? Are you on any asparin or ibuprofen etc?

Do you have any numbers for your

Liver: eg AST,

Kidney: Creatinine or GFR

LDH

I hope your doctors get to the bottom of this quickly!!!

God bless you

Skipro

[AussieNeil Partner Administrator in reply to Jotame]

From those results, I don't see how your specialist considers venetoclax to be failing. Your lymphocytes are very low and have fallen further. What's concerning is the drop in your other blood counts, so indeed it will be interesting to see what happens now that you have stopped taking venetoclax and what your BMB shows. You may be able to recommence taking it at a lower dose. Your platelet count is still acceptable, but you have just dropped below the recommended threshold for packed red blood cell transfusions to maintain your haemoglobin above 80. (Platelet transfusions are recommended when platelet counts drop below 20 if you have an infection and 10 otherwise).

Confirming that in Australia, CLL expertise is largely in the public sector. Associate Professor Bryone Kuss heads the CLL research team at Flinders. researchnow.flinders.edu.au...

Neil

[Jotame]

Thanks to you both. I will certainly post an uppdate when my BMB results come in.