What causes neutrophils to go so low after Obinutuzumab?

[PhotonPal]

This is kind of a geeky question but has really been preoccupying me following a first Omab infusion that took my N count to zero for several days. I'd like to understand it before deciding to continue this therapy. A number of members have also reported their neutrophil counts going way low following their first infusion.

I have not yet found a convincing explanation for why that happens. It seems counterintuitive given that neutrophil cells don't have the CD20 on their surfaces and therefor should not be directly targeted by Omab.

Here are some of the possible explanations I've heard so far from discussions with doctors or from medical journal articles:

1 - Omab activates neutrophils to eat up the antibody-marked B cells and after munching them, the neutrophils die.

2. The Omab triggered a cytokine storm that in turn triggered neutrophils to dive from blood vessels into the surrounding tissue, depleting them from the circulating blood.

3. Killing off of B cells by Omab triggered production of more in the bone marrow, taking BM resources away from production of more neutrophils - a competition for resources argument.

4. Immature and unactivated neutrophils are retained in the BM, or even called back from circulation. Possibly related to item 3.

5. High-affinity Fc receptors may mediate more vigorous ADCC on normal and malignant B lymphocytes with the release of granzyme and lysozyme, and neutrophil death via a bystander effect. (From a journal article).

6. Active infections. In my case it turned out that I had an active tho unsuspected gallbladder infection, which may have contributed to lowering my N count by attracting more neutrophils out of the bloodstream.

Thanks for any thoughts about most likely causes of neutrophils being deeply depleted by Obinutuzumab.

Paul

[PlanetaryKim]

I have wondered the same thing Paul. Thanks for posting this question and the various theories. They are all good ones. I will probably be starting Rituximab soon and am concerned it may have this effect n my neutrophils.

[PhotonPal in reply to PlanetaryKim]

Seems like it could, given that it also targets CD20. All the best with your therapy!

[PlanetaryKim in reply to PhotonPal]

Thank you. You too!

[bennevisplace]

Good question, probably one that most of us have never considered. It seems to be unsolved.

A quick trawl on Google threw up this for Rituximab, an earlier MCA targeting CD20

ncbi.nlm.nih.gov/pmc/articl... which suggests circulating antibodies in plasma cause neutropenia during treatment or several months after.

[EugeneL2 in reply to bennevisplace]

Thank you for the link to the article. I found this 2018 article discusses other possible mechanisms:

The mechanism of late‐onset neutropenia is linked to inhibition of granulopoiesis with a maturation blockade in the bone marrow [70]. The hypothesis that late‐onset neutropenia could be due to a defect of granulopoiesis linked to a competition with intra‐medullary B lymphopoiesis has been voiced. This hypothesis was sustained by more intense B‐cell activating factor (BAFF) elevation in patients with late‐onset neutropenia [69, 73]. Other authors have hypothesized that late‐onset neutropenia could be due to autoantibody production against neutrophils progenitors [74, 75]. Finally, large granular lymphocyte proliferation was observed in several patients with rituximab‐induced late‐onset neutropenia [26, 68]. This could explain late‐onset neutropenia as large granular lymphocyte oligoclonal proliferation is known to induce neutropenia [76].

link.springer.com/chapter/1...

[bennevisplace in reply to EugeneL2]

So neutropenia is BAFF-led? Me too. someone give me the idiot's guide. Still, if the experts are unsure of the mechanism(s) it must be complicated.

My neutrophils are still only 0.6, almost 5 months after finishing six cycles of FCR in the FLAIR trial. The low point was 0.1. According to the study nurse the main culprit is Fludarabine, but maybe Rituximab is driving late onset neutropenia?

[EugeneL2 in reply to bennevisplace]

BAFF is just one possibility, other possible reasons are autoantibody production against neutrophils progenitors and large granular lymphocyte proliferation. The authors were not sure which one.

[PhotonPal in reply to EugeneL2]

Thanks EugeneL2, I read that article and a few in its reference section. It's a vein of investigation I hadn't run across. Still no 'smoking gun' but I'm impressed by the range of theories about what causes late onset neutropenia. (I love the old saying that I don't know the solution but I'm impressed by the problem). I'm focused on the more immediate neutropenia, but these LON articles certainly could relate.

Paul

[PhotonPal in reply to bennevisplace]

Thanks bennevisplace, I had not seen that article and it's a nice review of theories on what causes rituximab induced neutropenia, with references.

Paul

[zaax]

They drop on Ibrutinib as well, mine dropped from 0.8 to 0.5. for a few weeks and then on the 3rd week they were at 1.0 and after about 6 months they were in the normal region.

[PhotonPal in reply to zaax]

Thanks zaax.

[Hidden]

I really like the way you think, and all of your hypotheses seem plausible.

Another possible outlook/circumstance, partly playing off what you have already said:

When you start with low neuts, and bone marrow is already impaired, inflammatory reaction (cytokines are one part of this) results in death of multiple immune cells in large number both from being activated and also just killed off by the extreme immune reaction, high fever, etc. i.e. seems multifactorial

And, sometimes what the body does in relation to trouble is not logical. We like to anthropomorphize that everything the body does has an intelligent reason behind it, but sometimes things just go haywire, and the body can't respond logically, especially when underlying conditions are already pathological.

[PhotonPal in reply to Hidden]

Thanks for your thoughts on this, hawkeagle. I really appreciate your experience around CLL.

Paul

[Hidden in reply to PhotonPal]

Thanks, and back at ya! I think your depth of knowledge into specific physiological processes regarding this topic is deeper than mine, but my observations are from a more diffuse overall view.

While we would like to know if it is because of this or that, sometimes it is because of this and that, plus several other things all together!

Regardless, a lot more remains unknown than known and it is noble to try to pin things down

Like herding cats!

[PhotonPal in reply to Hidden]

I so appreciate what you're saying about the complexity of the causes of neutropenias after mAb therapies. I tend to go down rabbit holes for the underlying causes of things, and on the neutropenia topic I'm getting the sense that there are so may possible causes (and probably it's multiple causes contributing) that I may shift my focus to clinical management rather than cause.

BTW, during my hospitalization with low neuts I received daily granix to stimulate production of more WBC's. That raised my neut count gradually, but also the WBC count overall, as expected. That got me wondering if such stimulation works against the purposes of the obinutuzimab therapy by boosting the number of CLL cells. If so, a series of Omab infusions - each followed by injections of granix - would probably result in a neutrophil count that bounced up and down like a sawteeth. Do you have any leads on whether stimulation therapy weakens the efficacy of mAbs?

Thanks - Paul

[Hidden in reply to PhotonPal]

No idea on either count:

Speculating regarding whether GCSF stimulates CLL cells: Possible, but not really directly related since B cells are different lineage than neutrophils, not descended from granulocytes. And CLL B-cells are self cloning. Do they even come from the progenitor stem cell process?

[AussieNeil Partner Administrator in reply to PhotonPal]

Your count of neutrophils is included in your WBC count, so you need to separately monitor your lymphocyte count to look for any associations. Keep in mind that your lymphocyte count includes healthy B and T lymphocytes, as well as CLL cells and CLL treatments can adversely impact on T cell production.

G-CSF shots shouldn't affect your CLL cells for the reason Hidden notes; Lymphocytes originate from the lymphoid stem cell line and neutrophils from the myeloid stem cell line, plus CLL cells proliferate for the basic reason that they are cancerous and no longer respond to control signalling that normally would stop them from dividing: en.wikipedia.org/wiki/Haema...

en.wikipedia.org/wiki/Haema...

Thanks for the interesting discussion!

Neil

[PhotonPal in reply to AussieNeil]

Thanks for clarifying, Neil

Paul

[PhotonPal]

Ah, I get it. I just looked up Granix, and it's equivalent to Neupogen, which is supposed to stimulate mainly the production of neutrophils.

Thanks!

[MsLockYourPosts Passed Volunteer]

It seems that the one given with CLL is that there are no known givens. I got rituxan when first diagnosed, and more recently obinutuzumab. My neutrophils were fine. A friend who was getting obinutuzumab at the same time as I was did well during the infusion but ended up dealing with LON (late onset neutropenia) after finishing her infusions.

[PhotonPal in reply to MsLockYourPosts]

Yes, I'm learning fast that there are so many variables dealing with blood cancers and their therapies, that at some point I just need to say enough investigation, and based on the best info I can get from all sources, I'm choosing this therapy. It feels a bit like 'winging it' so it's uncomfortable.

Thanks!

[Smakwater]

Good one PhotonPal,

Shall be waiting for that exceptional "simple version" answer.

JM

[PhotonPal in reply to Smakwater]

It is likely to be a long wait. My list of possible causes for neutrophil crash was fairly long when I started this post, and thanks to participants there are now a few more theories. When I started studying CLL/tests/therapies I was under the impression that the patient's biomarkers would point to one therapy as being the best. That might be possible someday when we have vast databases of patient's markers and clinical results (that's the hope of 'precision medicine', I think), but we're nowhere near that point, so there's a big dose of uncertainty in choosing a therapy. Which helps explain why there is so much switching of therapies. Aargh!

Be well,

Paul

[Hidden in reply to PhotonPal]

Dr Brian Koffman says it well. This is not verbatim, I hope I have not bastardized his meaning:

With CLL you are sometimes faced with life or death decisions with little information to go on, and multiple conflicting opinions.

I find this so true. it is an ongoing exercise in partially educated guessing.

One bright side aspect of this is that the newer therapies for which we do not yet have long term and resounding clinical evidence seem to be working very well on the whole, and a heck of a lot better than the limited choices even just a few years ago. And more is coming along.

[PhotonPal]

Educated guessing seems an apt description.

Re progress in drug development, following the conventional wisdom I waited as long as I could to have treatment (3 yrs), and as I started to think about treatment I was happy to realize that in that time more CLL drugs came on the market. Lucky timing.