Marrow Cellularity, normal and hyper levels?

[EPguy]

My BMB from Dx had a note "hypercellular". This is typical for PV and for a senior I had thought was usually over 70% to be Hyper. Cellularity goes down with age where 70% might be normal for a very young person while 30% is for a very old person.

I recently asked Dr whether there was a % reported in my BMB. There was and it was 40-50%. I had expected 70-80%

In the refs below, 40-50% is fairly centered in normal for a ~61 year old, not hyper, or even mildly hyper in my reading.

* Are any members aware of their result here, and any info that came with it?

In reports I've seen, ET ranges from normo-to mildly hyper cellular, while PV more likely is hyper. This is in the WHO Dx standards. But it's hard to find % values with these.

--

sciencedirect.com/science/a...

The mean cellularity began at approximately 50% in the third decade of life (20s) and then decreased ±2% per decade to 40% in the seventh and eighth decade (60-70s), but the normal range was very wide (30–70%).

--

onlinelibrary.wiley.com/doi...

Several studies (13, 14) defined cellularity cutoffs from less than 30% for hypocellular, 30-50% for normo, and more than 50% for hypercellular bone marrow, which is suitable for a population of patients aged about 70 yr. This is in accordance with our patient cohort

[MCW22]

I've only had one bmb and it reported 100% hypercellurality. I have no idea what that means.

Carol

[EPguy in reply to MCW22]

I added some more context, see my replies to my own post. So 100% means your marrow is all dots of the sort seen in the purple colored image.

[MCW22 in reply to EPguy]

I find this all too complicated to understand, but I'm geussing from that, 100% cellurality is not good then? My report also said grade1-2 fibrosis but specifically said NOT transformed to myelofibrosis. This BMB was over 3 years ago and shortly afterwards I was taken off Hydroxycarbomide and put on Ruxolitinib.Carol.

[Cja1956 in reply to MCW22]

That certainly doesn’t make sense to me. I don’t know your other numbers, but I always thought if you’re showing fibrosis that you are progressing to myelofibrosis. Maybe it’s time to get a second opinion.

[MCW22 in reply to Cja1956]

I did always think the report contradicted itself, and as my white count is always in the high 20s I did wonder if they suspected I might be about to progress, hence being changed from hydroxy to ruxolitinib. I didn't worry about it too much though because ruxolitinib would be the right drug for mf anyway.

Carol.

[EPguy in reply to MCW22]

I don't understand it too well either, but since it's in our BMBs at least we can have some context, so I tried to figure it a little bit. I agree less should be better, but I think fibrosis is tracked more carefully.

Did Dr say why HU was stopped? Probably your blood counts indicated the change.

Has your Dr discussed interferon? For early MF, if you may have that, it can be effective for some, and for some it can reverse fibrosis (and cellularity) over time.

[MCW22 in reply to EPguy]

No the consultant didn't say why I was being changed from hydroxy to rux and I was so shocked at the immediate change over that I didn't ask for a reason, but at that time my white count had been consistently rising and by then was 30. After an initial drop to 17, they crept up again and now stay in the high 20s but everything else is in range and appointments are now reduced to 3 monthly by phone.

Carol

[Cja1956]

So I just looked back at my BMB from last year and it said “mildly hypercellular marrow 60%”. I am 66 years old and have post Et Mf intermediate one. No one ever told me what was normal what was not.

[EPguy in reply to Cja1956]

In the new plot below, 66 year old would be just under 30%. I think, esp for MF, the fibrosis level in the BMB is of more interest than cellularity. But it is good for us to have some understanding of cellularity.

Also we learn here of the different ways our BMBs are interpreted. Mine said Hyper for 61 years at 40-50%, while yours is "mildly" hyper for 60% at 66 years. So much of our journey is vague like that.

[Meatloaf9]

Hi, my BMB 4 years ago at age 68 reported 50% cellurality. I asked my mpn specialist what a normal result would be and he said 100 minus your age is considered normal, so I guess mine should have been about 32%, I have asked more than once and always got the same answer.

[EPguy in reply to Meatloaf9]

Your Drs method gives slightly higher % than the plot below. But both are similar.

Did your report categorize it by "hyper" or "mildly hyper"?

By same answer, you mean Dr says to just apply the formula?

[Meatloaf9 in reply to EPguy]

My report only said cellularity 50%, was not characterized any other way. I don't remember my Doc's exact words but I think it was something like - it would normally be about 100 minus your age. I think he meant for people my age. Best to you.

[EssThro]

Greetings, EPguy.

Thank you for your many posts attempting to educate the community! I have been wondering how meaningful my cellularity data are, so this is timely for me.

I was diagnosed at age 72 and my BMB showed 50%, "slightly hypercellular for age." My diagnosis is ET/Pre-PMF, leaning toward the latter based on my mutation profile of 9% JAK2, 44% SRSF2, and 11/20 del(20Q). My cellularity and LDH (first tested several months later and found to be slightly elevated) also support Pre-PMF.

[EPguy in reply to EssThro]

You're right about how meaningful. My search on this suggests not as much as fibrosity. As noted above, labs seem to use slightly-, mildly- and hyper without a quantified meaning to those qualifiers.

Did you also get a fibrosis grade?

Understand on the SRSF2. My Dr (MPN specialist) does not consider LDH important for MPN. We have seen different opinions here.

[EssThro in reply to EPguy]

It's been a while since I looked at my BMB report. The detailed quote for cellularity: Normocellular to slightly hypercellular (50%).

My collagenous fibrosis was "absent" and I had "no significant increase in reticulin fibrosis." Apparently they rated it grade 0.

Yes, we do get different perspectives. My Doc is also an MPN specialist who thinks LDH is significant in differentiating Pre-PMF from ET, but not as concerned as I am about SRSF2 after I read various scholarly articles.

Thanks.

[EPguy in reply to EssThro]

By your provider's definition I would be well in the Normo range, it does seem arbitrary among the labs.

It seems at least for now you have no MF at all, since I assume you need some "F" to get there. Others may add better details here. But your Dr might suggest occasional BMBs to watch for any change there. I had "mild" 0-1 fibrosis, this is known in ET.

Is your LDH well controlled now? I had high at Dx (~400), I think my early 2020 covid and long covid may have had something to do with it. But it's top of normal at my last check.

In this reference, LDH became sigif only over 1000, it was focused most on non-progression hazards:

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

<<increased serum LDH level was associated with inferior survival, both as a continuous variable and as a categorical variable with the cutoff level of 1000 U/L>>

The plot they show is a good visual of the effect of very high LDH. But this is for overt MF.

In this ref, which include Dr Harrison as an author:

pubmed.ncbi.nlm.nih.gov/303...

<<Many pre-MF patients present as young adults, with thrombocytosis, elevated lactate dehydrogenase levels and increased bone marrow fibrosis (i.e. ≥ grade 1).>>

So if you had F=0 you are missing that hazard vs this report.

LDH vs Survival MF

[Aneliv9 in reply to EPguy]

So you have ET based on mild fibrosis??? Is the same as reticulin??? "I had "mild" 0-1 fibrosis, this is known in ET"

[EPguy in reply to Aneliv9]

I have a Dx of PV but an ambiguous reality. Other members have a similar blend. I think my listing of "hypercellular" had something to do with the PV Dx hence my interest to understand it more. ET is not usually with full "hyper" rather it's none or mildly hyper. But we've learned in this thread that this cellularity distinction is surprisingly arbitrary, hence what does the term mean here:

From the 2016 WHO PV crtiteria: "BM biopsy showing hypercellularity for age"

The age part is in the plot I posted below here.

For me other parts of my BMB point to ET.

--

Fibrosis has reticulin and collagen types. Collagen has a worse prognosis and is less common, from an older 2007 report:

<<Recent evidence has shown that the amount of bone marrow reticulin staining often exhibits no correlation to disease severity, while the presence of type 1 collagen, as detected by trichrome staining, is often associated with more severe disease and a poorer prognosis>>

sciencedirect.com/topics/me...

[Aneliv9 in reply to EPguy]

So your grade of fibrosis was MF0-1 equal to MF1? If so, is this compatible with ET?

[EssThro in reply to EPguy]

Very interesting information as always, EPguy. Thanks!I have only a couple minutes to respond so I will look at your links and may add more later.

Yes, it seems like no F should mean no MF. However, the definition of Prefibrotic PMF includes grade 0-1 F.

I think there must have been an oversight when my first bloodwork was done, so I do not have an LDH value at Dx. I was on 45mcg of Pegasys for 5 months before the first test (230), confirmed 2 months later. Four months later it was down to 185, and not checked since.

I was not aware of the strong impact of LDH on OS in MF. I look forward to perusing that study, keeping in mind that it applies to PMF, not Pre-PMF, having higher fibrosis than allowed in the definition of Pre-PMF.

[EPguy in reply to EssThro]

The def of prefibrotic makes logical sense, it can be before any fibrosis starts.

According to:

nature.com/articles/s41408-...

<<It (pre-MF) may be accompanied by a mild increase in reticulin fibers defined as grade 0 or 1>> Strangely grade zero can include an increase in fibers by this description. Maybe having any grade at all requires some fibers?

This ref has a higher typical pre-MF grade:

<<Many pre-MF patients present... with increased bone marrow fibrosis (i.e. ≥ grade 1)>> but is directed to young adults.

pubmed.ncbi.nlm.nih.gov/303...

[EssThro in reply to EPguy]

Thanks for the reply and links, EPguy.

Yes, fibrosis level is a continuum, not discrete amounts. If there are truly no fibers, it is clearly Grade 0. I assume that the cutoff between rated levels must vary between pathologists, location and pattern within the portion of sample examined. One rating of "not significantly elevated" may be grade 1 if a different section is examined or by another pathologist's opinion. I suspect that all of us MPNers have at least a small amount of fibrosis (scar tissue).

Regarding the second link, I was surprised to see that some experts would classify grade 2 fibrosis as Pre- rather than overt PMF. It must have to do with the other parameters assessed for the diagnosis. I shouldn't be surprised, I guess, because grade 2 is also compatible with ET and PV.

[EPguy in reply to EssThro]

The inconsistency in subjective readings is well seen here also on describing cellularity.

For link 2, this is the full report you're likely looking at:

onlinelibrary.wiley.com/doi...

There is a reference to Grade 2 fibrosis in patient 2, but this patient was placed as PMF. Pt 3 (preMF) was grade 1 with only focal grade 2. Did you find a full grade 2 pre-MF?

--

It seems we all have some fibers to make the marrow function:

<<The most common fibers in the bone marrow are reticulin and collagen type I/III>> for providing a connective tissue structure and a support for hematopoietic progenitor cells. So everyone needs at least some <<Grading of myelofibrosis was simplified by introducing four categories (including normal reticulin density)>> This would be 0,1,2,3 we are familiar with, and clearly 0 is "normal" and greater than 0.

What we care about is <<pathological increase in bone marrow stromal fibers>>

I didn't realize some level of fiber is always ok, and in fact required. It does mush up the judgement since there will near never be a "none" result.

--

Further in here <<the amount of bone marrow reticulin shows little correlation with the severity of the underlying hematologic disease while the presence and amount of collagen fibers are strongly correlated with abnormal blood counts and poor outcome. >>

So reticulin is reversible, and benign if one reads it literally. They don't say how it's reversed, I assume either IFN or Rux.

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

[EssThro in reply to EPguy]

Yes, some articles state that fibrosis reductions have been observed with INF.

It's been good communicating with you, EPguy.

[Aneliv9 in reply to EssThro]

Is these mutations more relevant to pre-PMF than ET?

[EPguy in reply to Aneliv9]

Fibrosis and cellularity are not mutations by the definition relevant to MPN, that's our Jak2, CALR etc or non-driver mutations in our DNA.

It seems to me the experts are still loose on clear Dx of Pre-MF or ET, and according to the report above, collagen is the one to look for. But I think there is more to it that that.

I would think you need at least some "F" of some type to have a Dx of MF, although having some F does not mean we necessarily have any sort of MF. Others here may be able to add to this.

-All this is unsatisfyingly vague because the nature of MPN is so often vague.

[EssThro in reply to Aneliv9]

Hi, Aneliv9.

If you were asking me about SRSF2 and deletion on chromosome 20, yes. I believe SRSF2 is present in less than 4% of ET with the JAK2 driver, but in 15-20% of similar Primary MF cases. There is a similar relationship with del(20Q) where less than 2% of ET/JAK2 cases have that karyotype. Having both of these in ET is very unlikely.

I have spent a lot of time thinking and researching these conditions and the available data on progression to overt PMF, transition to AML, and overall survival. I am at the point where I am accepting the fact that, at age 73, the median OS for my disease is between 3 and 9 years and I am better off if I just stop all of the investigating, follow my doctors' orders, and enjoy my relatively good health for as long as it lasts.

Time to meditate!

Good luck to you!

😴

[EPguy]

I looked into cellularity some more. Only a real hematologist can know this stuff properly. But one patient's view:

Our marrow has hematopoietic tissue and fat. Hematopoietic tissue is the cellularity and is where new blood cells are formed. As we age there is more fat and less hematopoietic tissue. My take is when there are too many of these cells per age, they are too productive and there is too much blood parts, this being the high counts we try to control. There is likely lots to more to than this however.

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

The plot here shows normal cellularity vs age. (see next reply for what too much and too few cells look like.) It's the best reference I've seen for this so far. Others say from age 50, subtract ~10% from 50 per decade. Member Meatloaf9 Dr says 100 minus your age. All close if not the same.

--

All this is about what cellularity is, but what it means is another thing. I'm not sure even the experts fully know this answer.

High cellularity is a diagnostic for PV vs ET. It's also something that can be reduced for some with IFN therapy. The other item they look for in BMB is fibrosity. This looks like strings among the dots and is the "fibrosis" of MF. The fibers of MF interfere with blood production.

Cellularity vs Age

[EPguy]

Image of too much and too few (Hyper and Hypo-cellular) in marrow. The small dots are the Hematopoietic tissue, white is the fat.

So 100% would be all dots.

(qualifier- this is my understanding)

CellularityComparison

[EPguy]

I'm exploring fibrosis levels, but came across more on cellularity levels that match better some of those posted here:

Age (years) % Hematopoietic area

20-30: 60-70

40-60: 40-50

≥70: 30-40

czemp.org/res/file/Thiele-E...

More evidence of such variation in these descriptions.