Disease Flare During Temporary Interruption of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia ( CLL ) - Pseudo Richters

[AussieNeil]

Several of us have reported our CLL symptoms have come roaring back after discontinuing Ibrutinib/imbruvica with even a few cases of what's been termed pseudo-Richters, where some patients appear to have even undergone unnecessary R-CHOP chemoimmunotherapy as our member Priss69 has reported: healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

Per this November, 2020 study report

academic.oup.com/oncolo/art...

with my emphasis:

"Rapid CLL progression following ibrutinib discontinuation has been increasingly recognized. This study demonstrates that similar flares in disease signs or symptoms may occur during ibrutinib holds as well."

Background: Approximately 25% of patients with chronic lymphocytic leukemia (CLL) experience a flare of disease following ibrutinib discontinuation. A critical question is whether this phenomenon may also occur when ibrutinib is temporarily held. This study aimed to determine the frequency and characteristics of disease flares in this setting and assess risk factors and clinical outcomes.

Conclusion: Temporary interruptions in ibrutinib treatment of patients with CLL are common, and one quarter of patients who held ibrutinib in this study experienced a disease flare. Resolution with resuming ibrutinib underscores the importance of awareness of this phenomenon for optimal management.

Awareness of this phenomenon among clinicians is critical to avoid associated patient morbidity and premature cessation of effective treatment with ibrutinib if the flare is misidentified as true progression of disease."

Some case studies

Two Distinct Clinical Patterns of Ibrutinib-to-Venetoclax Transition in Relapsed Chronic Lymphocytic Leukemia Patients

ncbi.nlm.nih.gov/pmc/articl...

Per this Chronic Lymphocytic Leukemia Treatment Algorithm 2022 healthunlocked.com/cllsuppo...

8. "A disease flare phenomenon, characterized by rapidly progressive symptoms and adenopathy and rarely histopathologic evidence of Richter transformation, may occur during interruptions in BTKi treatment, but particularly after stopping the covalent BTKi until the next line of therapy is started. We recommend continuing the BTKi during the transition period to next-line therapy, particularly through venetoclax ramp-up until the target dose is reached ."

With thanks to CLLerinOz and G-G of CLL/SLL Groups.io.

Note: Due to the need to increase awareness of this phenomenon, this is an unlocked post.

Neil

[LovecuresCLL]

Thank you for this important info. Are we seeing flares following cessation of Venetoclax?

[AussieNeil Partner Administrator in reply to LovecuresCLL]

I've not heard of this happening (yet) with Venetoclax monotherapy, but I presume it is likely to happen with all BTK inhibitors, with a further 12 in contention for approval following the success of Ibrutinib and Acalabrutinib: healthunlocked.com/cllsuppo...

[Sushibruno in reply to AussieNeil]

🤔😳😫

[AdrianUK in reply to Sushibruno]

If doctors are aware of this phenomenon it’s perhaps not quite as scary as it sounds. The trick here is to avoid stopping these drugs suddenly if at all possible, and avoid or minimise any treatment breaks wherever you can. And if it is not possible to avoid stopping the drug suddenly (eg due to a side effects) then you either just wait for the flare to settle or perhaps you might be able to prevent it by starting another cytotoxic drug immediately.

The reason we probably won’t see this with venetcolax and haven’t seen it wirh FCR, Rituximab or obinituzimab is that this is about the mechanism of action. BTKIs don’t really directly kill the CLL cells in the same way and to the same extent as other CLL treatments.

Think of a BTKI as a huge brake applied to the cell multiplication process. The cell tries to adapt to this. And so in some people it’s almost as though their cells are doing a “burnout”. Almost like the brake is applied but the cell is revving up it’s engine, as though it’s tires are smoking but it’s not going anywhere because the BTKI is stopping it.

Suddenly if you release that brake then in some cases those cells are going to steam off looking a bit like a drag racing car. And for a brief moment that cancerous lymphocyte behaves just like a DLBL cell and so looks and acts like it’s transformed.

But it hasn’t.

And so very quickly the extra activity will stop and it returns to a normal CLL type behaviour.

In a way this isn’t dangerous at all. As long as we all (doctors and patients) know what’s happening. The danger is we misinterpret what is happening, think it’s Richters and so panic into giving chemo that isn’t needed.

Of course these is such a thing as real Richters so the other problem is we mustn’t miss real cases, but presumably here the trick is if you think someone might be developing Richters and they are on ibrutinib to do the biopsy before stopping the drug to avoid this “false Richters” result. If you do the biopsy that way you’d know whatever results you got it wasn’t a flair going on because the BTKI hadn’t been stopped yet.

Also perhaps if switching to venetoclax from ibrutinib it may turn out to be wise to instead add the venetoclax before stopping. Though that is not technically licensed I can imagine a lot of doctors may decide it’s a great way to go in the future since venetcolax is so good at killing cll cells it might well act as a way to avoid the worst of the flair which I’m sure is quite a scary thing to experience, especially if you don’t know what is going on.

[Sushibruno in reply to AdrianUK]

Hi Adrian, I know that allot of people do very well on ibrutinib and for a very long time, but the more I hear about the negatives it has, the more I don't want to take it. Unless it's with a second or even a third med. I wouldn't want to experience this if it can be avoided, This is very new and I will be asking Dr. Lamanna if she has any knowledge on this. Cll can cause whatever it wants to our bodies and it's just terrifying. I mean im sure we' all feel this way it's the unknown that I really hate the most. I get anxiety but now it's with anger. I know I have to work on this but I'm sick of this disease. (I know it's for life) I know im coming across in a negative way but it's what I feel) My therapist will set me straight hopefully.

[AdrianUK in reply to Sushibruno]

Ibrutinib is a great drug. The fact that the cells can grow really quickly for a couple of weeks after stopping it is not really a reason not to use it in my view. You have to remember there are LOTS of people who use these drugs with little or no problems whatsoever. But for sure remember as and when it is time for treatment you have two big strategies to choose between. 1. Take a drug to hold back CLL hopefully for years of continuous use (acalabrutinib or Ibrutinib ) or 2. Take a combination of drugs to see if you can anihilate CLL and just maybe even get a cure or if not at least hopefully a long remission where you don't have to take drugs. Here if you are not a chemo candidate it is basically any venetoclax combination that you would choose. But remember whichever you choose you might need to use both options at different points. So for example anyone who doesnt get a great response to venetoclax combo is likely to be offered a switch to the other approach and similarly if you find the other approach isn't best for you as an individual you would be offered to switch in the other direction. Best not to get too attached to any one drug in my view especially as a younger person as you may well need several drugs over your lifetime.

Don't worry Dr Lama will help you every step of your journey. You are in safe hands!

[Sushibruno in reply to AdrianUK]

And u always make me feel better, thank you Adrian🙂. I can be very stubborn sometimes.

[AdrianUK in reply to Sushibruno]

It’s not being stubborn. It’s just being anxious and that’s understandable.

When I read posts about bad things that can happen I go thru a similar thought process of “oh no this might happen to me” then I have to find out more about it and then I can reason myself to a calmer place that realises these odd things are less likely to happen. Even this thing it’s only 25% which for a side effect type thing I agree is quite common. But it’s still 75% of people who even if they stop suddenly DONT get this. So when you get the facts and understand them better then it makes us feel less anxious hopefully.

[Sushibruno in reply to AdrianUK]

Thank you Adrian I'm always so thankful for all the education I get on this wonderful site🙂. Have a wonderful rest of the weekend.

[Schubert1870 in reply to AdrianUK]

I was so freaked out since I’m experiencing Ibrutinib flare, and would have overlapped I with V had I known instead of stopping the day before starting Venetoclax. I just hope the flare will dissipate as I ramp up with Venetoclax. The last time I felt these enlarged lymph nodes was when I began treatment in 2012, only now the pain is more acute. 😩

[Smith123456]

the reason i;m on imbruvica/venclexta/gazyva is probably imbruvica flare. I was on imbruvica for about 10 months when my local thought it was stopping to work. She started me on venclexta and then stop the imbruvica about 5 weeks in-which i did . My bloods started to jump within 3 weeks and i insisted adding my imbruvica back. The idea i was having 'flare' never occured to her or me. all my bloods quickly became normal again.

so i had an appt with my cll specialist shortly after and she had 2 thoughts, 1. i did not really relapse and she knew imbruvica/venclexta had synergistic effect. and 2 since i was already on imbruvica./venclexta combo which was not fda appoved , i might as well add gazyva and do the full triplet.

I am not on a trial.

[Sushibruno]

I wonder if all cll specialist are aware of this phenomenon, it's very serious and definitely very scary. They should do more studies on why this happens and hopefully find a resolution.

[AussieNeil Partner Administrator in reply to Sushibruno]

The 17 authors are from Mayo Clinic, so I suspect it will be read by CLL specialists - or perhaps they may read it here!

[Sushibruno in reply to AussieNeil]

Thanks Neil I'm gonna mention this to Dr. Lamanna.

[Zia2 in reply to AussieNeil]

Thanks Neil. This doesn't worry me anymore than Ibrutinib but glad I am aware of it. Something to discuss w doc but I'm sure she's aware as well. Thanks for posting! I'm grateful for these newer drugs!

[sllincolorado]

I hade huge flare - let’s call it an earthquake - when I discontinued acalbrutinib (similar to ibrutinib) in order to start a clinical trial. Huge and numerous nodes. Extremely painful. Oxygen saturation dropped to 85%.

I had to stop acala 8 days prior to trial. My flare up occurred almost immediately, showed no signs of abatement. Starting clinical trial improved the situation but has not fixed it.

I think the combo of the massive flare up and low oxygen saturation caused the the rigors and hospitalization to occur after the initial clinical trial infusion. Went home with oxygen, 10 days later needed a transfusion.

Two months later I am sort of back to normal but still have more and larger nodes than I had during 2 yr watch and wait and 2 yr of acalbrutinib.

I’m hoping adding venetoclax to the trial at the end of the month improves the node situation.

I’ve commented about this before but wanted to respond to this post since it is unlocked.

[Fwanni]

Thanku.v important and informative. My bloods hve been v stable during 18 months of inbrutnib. I had to stop it twice close together for skin op. White cell results post second 8 days had doubled , lymphocytes had jumped but less.

I was v taken aback , concerned. It will be interesting at next blood check in 3 weeks what it will 'do..

HannieB

[AussieNeil Partner Administrator in reply to Fwanni]

This post explains all the different white blood cell types that make up your total WBC count.

healthunlocked.com/cllsuppo...

From what you say, you can expect a more normal count next blood test, both due to the other counts dropping back and Ibrutinib again bringing your CLL under control.

Neil

[john-doe]

I have had disease flare several times when stopping Acalabrutinib for a week or so at a time to let neutrophils recover.

My lymph nodes flare from nonpalpable to plainly visible to the eye in less than week. Plus spleen area begins to hurt.

Where do the CLL cells that so quickly fill up my lymph nodes and spleen come from? Are they being pumped out from my marrow? Or can B cells multiply outside of the marrow?

[AussieNeil Partner Administrator in reply to john-doe]

Besides inhibiting CLL cell division, BTK inhibitors like Acalabrutinib also inhibit the signalling that normally keeps the CLL cells safely ensconced in the nodes and bone marrow. So when you stop a BTKi, not only do CLL cells recommence cloning, but they can also flood back from the blood into the nodes, spleen (a big, specialised node) and the bone marrow. The flare generally quickly reverses when you restart on the BTKi. Has that been your experience? Some find it takes a month or so for their nodes to return to the pre-flare state.

Neil

[john-doe]

If I return to full dose the nodes mostly return to normal in a week, the spleen taking a bit longer. But because of off-target effects (neutropenia) I am unable to return to full dose and so the disease progresses.

I’d hate to see what would happen in my current state if I paused Acalabrutinib.

Oh, OK so B cells can clone. Do you know if that cell division can take place outside of the marrow?

I am seriously looking into CAR-NK and my understanding from talking to one of the PIs is that a best case outcome is MRD- in PB but little to no change in marrow involvement. (As of July my marrow involvement was 5%.) So I am trying to figure out how good that outcome would be given that I have seen my disease flare in one week when off BTKi. A one week PFS would not be worth the trial but I take it the flaring is mostly isolated to BTKi.

[AussieNeil Partner Administrator in reply to john-doe]

CLL proliferation is mainly in the nodes, spleen and bone marrow. CLL is dormant in the peripheral blood.

I'm sorry to read of your challenge in your profile of trying to keep your CLL under control and it sounds like you'd be a good candidate for CAR-T or better yet CAR-NK. (I've shared the challenges of living with neutropenia and trying to stay out of hospital , but a combination therapy has worked for me.) Given you live in the USA, have you sought a free CLL Expert consult from the CLL Society? You may have mentioned it elsewhere in your replies, but you haven't noted doing so in your profile.

Neil