Ibrutinib is an immunosuppressive

[zaax]

I seem to be reading that amongst other things Ibrutinib is an immunosuppressive, is this right?

[SofiaDeo]

"Immunosupressive" usually refers to a drug effect, not a classification. Ibrutinib has immunosuppressive potential, but it is not classified pharmacologically as an immunosuppressive agent. Traditionally, "immunosuppressive agents" have been defined as those used to prevent solid organ transplant rejection, and treat autoimmune disorders. But many drugs can affect the immune system, inhibiting it to some degree, and ibrutinib is one of them. Steroids have immunosuppressive potential too, but we don't think of steroids as mainly immunosuppressants. Ibrutinib is being assessed for its' potential in solid organ transplant rejection prevention, but it's not currently classified as an "immunosuppressant".

[AussieNeil Partner Administrator]

Further to SofiaDeo's reply, all CLL treatments suppress the immune system, because they reduce the number of healthy B-cells as well as CLL cells, plus pretty well all treatments can cause neutropenia. Actually Ibrutinib has been found to improve T cell function, so it's actually better than most other CLL treatments in this regard.

Addendum: Per SofiaDeo's reply below citing four studies, it seems that other BTK inhibitors can also improve T cell function and it's not yet clear under which circumstances particular BTKIs do this.

Neil

[nvp815 in reply to AussieNeil]

Neil,Can the same be said for acalabrutinib as far as improving T cell function?

Hope you are doing well.

Thanks,

Nan

[AussieNeil Partner Administrator in reply to nvp815]

It seems that one of the off target effects not present in Acalabrutinib may be the reason behind the improved T cell function observed in one Ibrutinib study. That was disappointing to me, given I was on an Acalabrutinib plus Venetoclax and Obinutuzumab trial. However SofiaDeo's further three references below show that the situation is far more complex: healthunlocked.com/cllsuppo...

Further, as my trial specialist noted with respect to my immunity part way into the trial, it was likely better than prior to starting the trial, because despite having no detectable B-cells in my blood (the result of an immunophenotype flow cytometry blood test, not an MRD test), I would no longer have CLL suppressing my immune system.

CLL suppresses the immune system in multiple ways. Bone marrow infiltration suppresses the production of other white blood cells. CLL also exhausts T-cells and can change the CD4:CD8 T-cell ratio. It also suppresses plasma cell production, which is why many of us develop low immunoglobulin counts in watch and wait.

I finished taking Acalabrutinib and Venetoclax just over 6 weeks ago and had my last Obinutuzumab infusion 8 months ago. My neutrophil count is the best it has been in 15 years. My eosinophil counts have also recovered to normal. (In the past few years, my blood counts often recorded zero eosinophils). My basophil and monocyte white cell counts have also improved.

Interestingly, this month, my IgG was the highest it's been since I was diagnosed 12 years ago. I have weekly subcutaneous IgG, but it seems I might now be making more IgG immunoglobulin. My IgA and IgM are still at record lows, which perhaps indicates that previously suppressed plasma cells are now working better. My lymphocyte count is still very low, so I suspect I probably still don't have much in the way of B-cells, which would explain the low IgA and IgM. When our B-cells respond to infections/vaccinations, the new B-plasma cells first start producing IgM, then through what's termed class switching, they switch to producing IgA and IgG.

Neil

[nvp815 in reply to AussieNeil]

Thank you for your thorough explanation and for the update on your status. I am thrilled to hear you are doing so well. All the best,

Nan

[zaax in reply to AussieNeil]

From my reading, B-cells are the memory cells; B-cells produce a response to a virus / infection / vaccine which you had years ago, so they know what do and if they meet it again and may not notice their response. Therefore you must have B-cells otherwise you would get every infection going.

[SofiaDeo in reply to zaax]

There are memory B and T cells, and they are a subset of all B & T cells. And it's not really a "you are missing one cell type, so will get infections". Our bodies have multiple redundancies for the functions of the various immune cells. We are more likely to have immune system dysfunction because of the diseased B cells, but to what extent this affects infections/infection rates in patients can differ. And as bone marrow heals after successfully tamping down bad CLL cell growth, some of us may get some bone marrow function back that had been suppressed from the CLL crowding out everything else.

And this is true for the non-B cell types too. My platelets are hovering around 80, and I am not getting petechiae or bleeding gums or nosebleeds. But others may get them at these levels. There are often multiple factors that can contribute to any particular patient response.

[AussieNeil Partner Administrator in reply to zaax]

I simplified my answer to only relate to the stage in the B-lymphocyte lifecycle where CLL can arise. I must have some mature B-cells (plasma cells and memory B-cells), because I'm still making some immunoglobulins. These mature B-cells are usually overlooked with respect to CLL treatments, because they don't highly express the markers or use the pathways targeted by CLL treatments. SofiaDeo is correct. Our immune system initially relies on barriers to prevent infection; our skin, mucus, stomach acid, etc, then our innate immune system - our non-lymphocyte white blood cells , immunoglobulins etc. Lymphocytes are the smarter part of our immune system as they can recognise bugs they've seen before and infected or cancerous body cells. You are in part right that I am at increased risk of infection, with my clinical trial doctor telling me that I'll have next to no protection against new viral infections until my lymphocyte count improves.

[SofiaDeo in reply to AussieNeil]

I thought the consensus was still out on T-cell modulation, and that it could be a factor in some patients SE's while on ibrutinib. There was data in 2017 showing improved T-cell counts for certain types of T-cells, but some later studies showing the opposite.

A 2017 study showing increasing T-cell counts with ibrutinib:

jci.org/articles/view/89756...

2018 study that waffled a bit on the answer IMO

ashpublications.org/blood/a...

2019 study, but in mice, showed the opposite:

jimmunol.org/content/202/1_...

And a mid Aug 2019 preprint study in mice, was looking specifically at T-cells as related to aplastic anemia, also concluded that ibrutinib (in these mice, anyway) suppresses immune cells. It includes a comment (with reference) that ibrutinib is used in some acute GVHD as well as some T-cell-mediated chronic GVHD cases, because of the drugs effect on T-cells.

nature.com/articles/s41423-...

My take on all this is, depending on the patient & their particular genetics, there may or may not be increased T-cells counts for the various types of T-cells.

[AussieNeil Partner Administrator in reply to SofiaDeo]

Thanks for supplying all those relevant references. They can give us some hope that whatever BTK inhibitor we are on, our T cells may work better. Hopefully, eventually we will know which markers predict this. Meanwhile, there are tests that can check our T cell counts (immunophenotype flow cytometry test) and CD4 to CD8 T cell ratio.

Neil

[bennevisplace in reply to SofiaDeo]

I revisited this after the question surfaced again in a post by zaax healthunlocked.com/cllsuppo...

The references you cited reach different conclusions, making the point that the picture is far from clear. Forgive my naive questions and observations, but the waters may be muddied by differing methodologies and potential conflicts of interest:

jci.org/articles/view/89756...

- CD4 and CD8 T-cells are INcreased in peripheral blood - how meaningful is that after BTKi has flushed CLL cells out of other compartments?

- Effect is seen with Ibrutinib but not Acalabrutinib - a plethora of author affiliations with Abbvie/ Pharmacyclics, Janssen (Ibrutinib)

ashpublications.org/blood/a...

- CD4 and CD8 T-cells are DEcreased in peripheral blood samples treated further in vitro - how meaningful is in vitro?

- Effect is seen with Ibrutinib but not Acalabrutinib or Zanubrutinib - One of the authors has affiliations with Abbvie/ Pharmacyclics, Janssen (Ibrutinib)

jimmunol.org/content/202/1_...

- This one looks at T-cell function not just numbers

- T-cells INcreased by BTKi in mice with a particular lymphoma

- Ibrutinib, but not Acalabrutinib inhibits function of T- and NK-cells - one of the authors is affilated to Acerta/ Astrazeneca (Acalabrutinib)

Here is another paper, concluding that long term Ibrutinib therapy reverses CD8+ T-cell exhaustion, which I guess is a good thing in replenishing the patient's stock of functional cytotoxic T-cells frontiersin.org/articles/10... No conflicts of interest declared this time.

[cajunjeff]

Killing the bad cells and sparing the good cells is challenging. Chemo treatments are very much like dumb bombs in this regard. Chemo can’t tell the bad cells from the good cells. Chemo is very immunosuppressive.

Ibrutinib is more of a smart bomb, a bomb with a guidance system dumb bombs lack, which targets cancer cells. But it’s not a perfect smart bomb. It can have collateral damage, like the bomb that takes out the headquarters of the terrorist headquarters, but knocks out a nearby school too. In furtherance the chemo analogy, chemo is taking out the whole town, not just the neighborhood where the terrorists live.

All of our Cll meds come at a price. If we play the bad hand of cards we got right, we can compensate for our impaired immune systems and live normal lives.

[ANA4 in reply to cajunjeff]

Thank you for always lifting me up 🌹

[lankisterguy Volunteer]

Both SofiaDeo and AussieNeil have provided excellent answers. I would add that the links and research studies below add more detail to those descriptions. -

I would opine that our immune system is incredibly complex and we can have one drug that supresses one portion of immunity and improves another. The links below detail that CLL patients on Ibrutinib get fungal infections in their lungs more often, but as AussieNeil points out, Ibrutinib also seems to reverse the action of CLL making T-cells exhausted. And some organ transplants and CAR-T therapies are using Ibrutinib to reduce Graft vs Host reactions from the immune system.

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pubmed.ncbi.nlm.nih.gov/289...

mdedge.com/hematologynews/n...

academic.oup.com/cid/articl...

ascopubs.org/doi/10.1200/JC...

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Len