Has anyone been on the combination therapy of Venetoclax, Ibrutinib and Obinutuzumab?

[Time17]

I was wondering if I could hear from someone who has had the combination of Venetoclax, Ibrutinib and Obinutuzumab (Gazyva). My CLL is completely resistant to Chemo and actually continued to spread while I was on FCR. Basically I have a rare c-myc mutation for CLL that has a poor prognosis. I have been put onto Venetoclax and at the beginning of week 4 of my treatment I do not seem to be getting a response—lymph nodes still hard. My Haematologist is looking to introduce Obintuzumab (Gazyva) the week after I go onto the full dose Venetoclax. He says he’ll switch me to Ibrutinib if I do not respond to Venetoclax. From the research it seems that combinations are the best way to go and my Haematologist agrees. So I would like to try being on a combination of all three of these drugs. However cost will also dictate if I can do these three drugs together. I am in Australia and the PBS will pay for one and the drug company will discount the second but the full cost of the third would be my expense. So I want to know has anyone been on this combination and the success rate.

[Hidden]

Lilly_Pad_Master is on a triple therapy now-i think acalbrutinib and not imbrutinib though

[Time17 in reply to Hidden]

Thanks for that.

[HopeME]

I think the combination of these three drugs is being used frontline in most cases and as part of clinical trials. I haven’t heard of anyone receiving the combination in a relapsed setting. That being said, given the promise this combination offers it isn’t surprising that you are seeking it out after relapsing on chemotherapy. I wish you all the best.

[Time17 in reply to HopeME]

Thanks for that info. I hadn't had any luck finding anything on relapsed CLL/SLL trials for this combination either.

[HopeME in reply to Time17]

I’m visiting Dana Farber in Boston for my 3-month check-up next week. I had BR treatment last year at another institution. I’m in remission presently and feeling wonderful but that won’t last forever since I am trisomy 12 and unmutated. I plan to ask my doctor if there are any clinical combination trials for relapsed patients in the planning stages anywhere in the US or the developed world. I’ll let you know what I hear.

Best

Mark

[Time17 in reply to HopeME]

That would be great. Very much appreciated.

[schmitthj007]

Hi Time17

I am on triple therapy as part of a phase 2 trial at Dana Faber Boston. But instead of Ibrutinib I am on Acalabrutinib a newer BTK inhibitor. Overall the therapy is well tolerated, however, developed moderate neutropenia as well as moderate to severe thrombocytopenia needing steroids. The response was great with all my nodes gone and hemoglobin significantly improved also feeling much better.

[Time17 in reply to schmitthj007]

Thank you for replying. That's great news about your response to the triple therapy. The side effects while frustrating are still better compared to some of the chemos I've had to endure. From what I have read about Acalabrutinib its sounds very promising. Your response to the triple therapy is similar to another participant on the trial who contacted me. Hearing your your news gives me confidence to go down this path if it is possible cost wise.

[closh]

I'm in Australia too and have been on the double combination of Ibrutinib + Venetoclax. Ibrutinib clears out the nodes very quickly (ie they shrink in days) and the Venetoclax kills off cells quite efficiently in blood and marrow. Most people on our trial got to MRD-. They've found one mutation that the few people who've progressed since treatment have all had and are now able to test for that.

I'm not sure who your doctor is but for a difficult case like yours, I'd suggest getting a second opinion from Dr Con Tam in Melbourne. He's the "guru of CLL in Australia", runs combo trials and also has good connections with the drug companies.

Graham

[Time17 in reply to closh]

Hi Graham. Thanks for replying. My Haematologist is based in Brisbane at the Wesley hospital. I live in Bundaberg so I am always travelling to Brisbane for treatment but my Doctor does come to Bundaberg once a month and I have been able to have some of my chemo treatments locally.

I have some knowledge on Venetoclax but from what I have read Ibrutinib seems good at clearing out lymph nodes which matches your response to your treatment. I have a lot of CLL lesions in my bones throughout my body and it has spread through my bone marrow to organs and lymph nodes as well. However my lymph nodes are not too large at this stage. So far my doctor has been very open to all treatments and has been consulting with other Haematologists so this has given me confidence but I eventually would like to deal with someone who specializes in CLL/SLL. So thank you for letting me about Dr Tam at Peter Mac. At the moment my priority is to get this disease under control ASAP so I really believe it has to be a combination therapy. From my reading my preferred combination is V+I and Obintuzumab but working out how to pay for this is going to be a challenge.

Are you still on the drug trial for your Venetoclax/Ibrutinib combination and has your Haematologist spoken about adding any of the newer Immunotherapy drugs such as Obintuzumab or Ofatumumab to your treatment regime?

Do you know if your trial is still open ?

[closh in reply to Time17]

The I+V trial I'm on is closed. I don't know if any more are planned.

I'm on either Ibrutinib or a placebo - I honestly don't know. Everyone who got to MRD- (almost everyone from my cohort) was randomised to this. If we start progressing again, we get ibrutinib or Venetoclax added back in. The aim of the trial was ideally to cure CLL but if not, to see if episodic treatment would work ie just get 12 months treatment every 5+ years until you die of old age.

I travel from Adelaide to Melbourne for treatment and first went there just for a second opinion from Dr Tam, after I wasn't confident about my local Haematologist's advice. One very useful thing is that they've set up much more detailed CLL testing than is available in Adelaide, and I suspect the rest of Australia. I had IGHV mutation testing and NGS testing of around 50 genetic markers before treatment options were offered.

If you had this level of testing, you might get a better recommendation? It would probably explain what you are resistant to.

For the I+V combination, they've very recently discovered a new mutation that signals resistance. They are now testing all trial participants for this - I doubt many Drs would be aware of this and so in a situation like yours, I'd spend the airfare and a few $ to get some advice from a research specialist. You can still probably get treated in Qld but under advice from Dr Tam. If he has a suitable trial available, they cover all airfare and accommodation costs - it's a great arrangement (apart from too many CT scans, but that's the deal).

Graham

[Time17 in reply to closh]

Hi Graham

I going to have a chat to my Haematologist at my next appointment about a referral to Peter Mac and Dr Tam and see if he can work with him. I really believe it's worth it as I definitely want to go onto a combination therapy that is best suited to my mutations.

You certainly had a win getting onto your drug trial. I was amazed to learn that they cover airfare and accommodation costs.

Thanks for all your advice, it has been very helpful.

Trevor

[closh in reply to Time17]

Just thought I should mention that I found out about the pending trial during an appointment with Dr Tam. I said I'd be very interested and to keep me in mind if it's approved. When it was approved, he was only allocated 4 slots from 12 worldwide for the first cohort and he called me to say he had a couple of desperately ill patients that he wanted to put in first. That was fine by me (of course). About a month later, he called to say some of the US centres were being a bit slow in filling their spots and so said if I could come over for assessment he'd look to get me in. It's worth being on the radar with the people who are organising the trails.

I was also surprised that they covered costs and would have been fine paying my own flight and accommodation costs. Apparently it's an ethics requirement in Australia so that trials don't discriminate based on financial resources of the patients.

Graham

[Time17 in reply to closh]

Hi Graham

Just had an appointment with my Haematologist and he is happy to refer me to Dr Tam at Peter Mac for a second opinion. He said I would have more chance of getting onto a drug trial if I was with the team at Peter Mac. So thank you for your advice about the trials at Peter Mac.

[fell in reply to closh]

Hi Graham, do you know the name of the mutation for which they are testing? I’d like to ask my trial doctor about that and whether or not I have been or will be tested for it.

Thanks,

Fell

[closh in reply to fell]

Hi Fell. Sorry - I'm not sure what the actual mutation is. All I know is that during my last appointment in March, they mentioned that all of the patients (think there was only a couple though) who'd progressed on I+V to date had this newly identified mutation and so they were checking everyone. They said results would take around 2 months. I doubt it's in any published literature yet and I'm not sure what the approach will be for those with this mutation - my next appointment's not until June.

I'm also not sure how they do the mutation testing on those of us with UMRD- (ie no CLL cells in the samples)?

I find out different depths of information depending on who I see for my appointments. Dr Tam knows his patients from these forums like to know all of the technicalities but his Registrar (who I often see, as I'm now a simple case) takes the annoying approach that her patients require reassurance rather than information and we wouldn't understand the information anyway.

Graham

[fell in reply to closh]

Thanks, Graham. I am going to ask my doctor about the test. Your comment about the registrar made me shake my head. How incredibly patronizing of her!

Best,

Fell

[Hoffy]

I plus V working very well for me. I am 17P deleted and Unmutated,

I am not sure how much Obintuzumab (Gazyva) helps,

Be well,

Hoffy

[Time17 in reply to Hoffy]

That's good information to know. Thanks for the reply.

[closh in reply to Time17]

I think the previous O+I+V trials used Obinituzimab first to reduce tumour load. That hasn't been necessary for those on the I+V trial and I have wondered whether it would be best adding the O in last to attack any remaining CLL cells instead?

[Jbuckner-75]

I am on a trial now with all three drugs. So far so good. Numbers have went down and lymp nodes reduced. I start Gazyva in a few weeks.

[Time17 in reply to Jbuckner-75]

Thanks for letting me know. Did it take long for the lymph nodes to reduce? One month down and some of mine are still there original swollen size.

[Jbuckner-75 in reply to Time17]

It only took about a month if that for mine to go down. But I only had one and it wasn’t huge yet.

[Time17]

That's good to know, thanks.

[Lu05]

Just wondering how you got on with these , I am to begin a trial CLL17 on the 7th of July these are all arms of treatment that you mentioned I will only get one and as yet do not know which one x I’m curious as to how you are doing now 🙌