Is CH(Clona Hemopoesis)complication common for stage IV blood cancer?

[sunsetssr]

I found some interests on my former post about CH/Clona Hemopoesis, and if I'm not wrong the terminalogy for a lay person means "a faulty bone marrow" along side with blood cancer diagnosis.I thought if any blood cancer patient is diagnosed as stage IV, we can assume the bone marrow is involved and faulty. I got very concern when my Oncologist shared her suspecious about CH coming to the picture on my cancer journey. I appreciate any feedback and your experience in this area.

[AussieNeil Partner Administrator]

Sorry, but other than your post of 7 months ago about Clonal hematopoiesis (CH) healthunlocked.com/cllsuppo.... we only have this 3 year old post about Australian research concerning the risk of developing CH healthunlocked.com/cllsuppo...

Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL ashpublications.org/blood/a...

Neil

[LeoPa]

I don't know about CH but if your hemoglobin and red blood cell and platelet levels are tanking then your bone marrow is definitely faulty in one way or another (unless the reason is internal bleeding). I don't think that a stage 4 blood cancer is possible with a completely healthy bone marrow. So in that sense yes. There is definitely a link.

[sunsetssr in reply to LeoPa]

Thanks for your reply. My RBCs and Hg, are fairly normal but LDH is high, platelets and WBCs are very low. I asked my Oncologist how it could be faulty bone morrow when part od tests is still fairly normal? Her response was "we do need another Bone marrow biopsy"

[LeoPa in reply to sunsetssr]

Do you have CLL? WBC very low would be strange with CLL.

[sunsetssr]

Thanks for your reply. Initially diagnosed as CLL, 11 years ago,but gradually narrowed to Marginal Zone Lymphoma (MZL) and later to Spleenic Marginal Zone Lymphoma. My WBCs were within normal range before treatment and now between 2.5 -3.2 on my monthly lab.

[PoisonDwarf]

Hi sunsetssr,There are a number of possible answers to this question, so I'd suggest clarifying with your Oncologist what she meant by CH.

Have you had a bone marrow test recently or other testing because there's been a change in your symptoms or treatment has stopped working?

You mentioned stage IV. CLL/SLL is a blood cancer because it causes malignant B cells in the blood which are clones or faulty copies originating from lymphoid stem cells. All hematopoietic stem cells originate in lymphoid tissue, mostly bone marrow. As Leopa says, faulty bone marrow & a diagnosis of a blood cancer go hand in hand.

CH means clonal hematopoiesis. The clonal bit simplistically put means faulty copies of the original & all identical. CLL can turn into a more aggressive form, although it still follows from the lymphoid line.

The paper Neil posted mentions both lymphoid & Myloid lines. Following treatment a more aggressive mutation can occur, although it's never guaranteed.

Bone marrow contains lymphoid & myeloid stem cells. Both can get damaged & produce faulty clones from either side.

Myloid stem cells or clones cause a different blood cancer, because they start from a different cell line. The majority of people unlucky enough to go on to develop cancer have one or the other not both. There's rarely a cross over.

There is something called CHIP ~ clonal hematopoiesis of Indeterminate Potential. This has grown as an area of health interest as one of the determinants of susceptibility to potential heart issues or diabetes. The important part here is that just because some change shows in the genetic testing it doesn't automatically mean that you'll have a heart attack! Just as having MBL or monoclonal b cell lymphocytosis doesn't mean developing CLL. They can now distinguish MBL from high count MBL. The high count increases the odds, but only at a rate of 1 - 3% a year. It's the same for Myloid defects.

What they have discovered from CHIP studies is that changes can occur in either lymphoid or Myloid cell lines, but it's also one or the other. Only very rarely does someone have mosaicism, where there's changes in both.

I am not a doctor or any kind of expert. As this is such a complicated subject & CH can mean different things your Oncologist is the best, if not the only person who can explain what she meant.

There maybe no reason to be concerned. It could well be that it's an expected progression as CLL advances. When you understand what she meant it can help reduce any concerns or anxiety. I hope at least this simple explanation will help you decide what questions you need to ask.

Best wishes.

[sunsetssr in reply to PoisonDwarf]

Excellent clarification. Unfortunately my hematologist is retiring,s o no more access to her, but hopefully I can get more details from the new one when I meet her. I had BMB, leass than a year ago and know the new oncologist will order a new one for me soon. It is hard to wait, but this post and all the people responded to me have helped me to have less anxiety so far. Hope I can update everyone when I get more information. Thanks again.

[PoisonDwarf in reply to sunsetssr]

I'm glad it helped in some small way. The waiting & not knowing is always the worst. 🫤 I hope your new oncologist gives you the explanations you need & soon! Please do keep us updated.

Take care.

[sunsetssr]

Thanks for your kind words and the time to explain. I'll update you all In upcoming month of Dec. This group is a life saver; my anxiety is much less knowing good people in this group willing to answer my questions and support me.Thanks again

[SeymourB]

sensetssr -

Clonal Hematopoeisis occurs in everyone, increasing with age:

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

Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

Blood. 2015 Apr 30;126(1):9–16

-----

Hematopoietic stem cells are where blood cancers start:

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

The dark side of stemness – the role of hematopoietic stem cells in development of blood malignancies

Front Oncol. 2024 Feb 19;14:1308709.

-----

It's probable that CH mutations are what starts CLL in the first place.

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

Age-related clonal hematopoiesis and monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia: a new association?

Haematologica. 2018 May;103(5):751–752,

-----

Lymphoid clonal hematopoiesis sees a different set of commonlt mutated genes than myeloid cells - in order of frequency:

"DUSP22, MGA, NCOR2, FAT1, ITPKB, Sin3A, KMT2D, ADD2, MYD88, FOXO1, NOTCH1, PAX5, SPEN, NOL9, IRF2BP2, ADGRV1, FAT2, IGLL5, LTB, ZFP36L1, BTG2, VAV1, PTCH1, NFKBIE"

onlinelibrary.wiley.com/doi...

Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations

Hematology, Volume98, Issue6, June 2023, Pages 951-964

-----

Most of the research on CH has focused on otherwise normal people with normal blood counts (CHIP) or those with cytopenias (CUSP). But the same processes continue to work in CLL, during, and after therapy.

CLL therapies, both CIT (cytotoxic chemo-immunotherapy like FCR) and long term targeted therapies can possibly lead to additional clonal hematoiesis via marrow suppression leading to cytopenias.

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

Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL

Blood. 2021 Sep 3;139(8):1198–1207.

-----

I suspect, but cannot prove that waiting too long before treatment leads to additional clonal hematopoiesic mutations that will give additional trouble in secondline therapy and beyond. I thought I had a reference to someone smarter speculating that, but I can't seem to find it.

For individuals, the type of sequencing of blood cells necessary to detect CH is beyond normal care. Major cancer research centers may do it. I had a panel of 172 genes sequenced by M.D. Anderson prior to treatment, but it did not include the most common genes I listed above. Maybe they'll come up with a future panel. In any case, insurance balked at reimbursing me for it, and we finally worked out a deal where they reimbursed for 5 or 6 of thmore well known genes, and MDA waved the cost for the rest.

I'll be asking them about CH gene testing, though.

=seymour=

[PoisonDwarf in reply to SeymourB]

Hi Seymour,Many of the major US cancer centres have CHIP Clinics & perform the DNA chip panels. MD Anderson has that facility for NGS testing.

I'm in Canada so all testing is publicly funded, which limits access an example of this is that genetic sequencing isn't done until it's time to treat. I discovered through my CLL specialist that they had created a CHIP clinic but were awaiting funding. To date that hasn't happened. I don't think I won the genetic lottery.

My reasoning was that the history of heart disease & cancer on both sides of my family is abnormally high & not simply due to poor lifestyle choices! Of nine cousins, one died before 50 & two just over 50. 2 from cancer, I'm the 3rd but all different types. The other cousin developed gestational diabetes that didn't disappear with delivery & left her with type 1 & heart disease.

Maybe I'll buck the trend.

[SeymourB in reply to PoisonDwarf]

PoisonDwarf -

Indeed, M.D.Anderson has a CHIP clinic:

mdanderson.org/documents/De...

M.D.Anderson Leukemia Insights, November, 2021

I get the impression that they do not do this testing in the presence of a hematological cancer, but when additional genetic variants showed up in other testing. The 172 gene NGS panel that I had was called EndLymphoma Mutation Assay by NGS, and it tests some of the CHIP genes. I presume that than panel plus CHIP testing is done after other cancer treatments that may lead to MDS or AML development.

But I'll ask them about CH testing in general to see what they say. I expect the answer will be something like, "We only do that as part of other research in CLL patients," at which point I'll volunteer.

I see 31 studies listed on the National Cancer Institute list of Clinical Trials:

clinicaltrials.gov/search?i...

One of them is a history study at NIH. I'm already enrolled in the History of CLL study there, so I may ask to join it.

clinicaltrials.gov/study/NC...

CHIP/​CCUS Natural History Protocol

But they might exclude me based on my CLL diagnosis:

"INCLUSION CRITERIA:

Greater than or equal to 18 years of age

Willingness and capacity to provide written informed consent

Presence of a somatic pathogenic variant associated with hematological malignancy

Variant allele fraction of greater than or equal to 2% in at least one identified somatic pathogenic variant

EXCLUSION CRITERIA:

Known diagnosis of a hematological malignancy or bone marrow failure syndrome (excluding MGUS or MBL)"

They seem to want to exclude in particular known MDS:

"EXCLUSION CRITERIA:

...

Morphological evidence of dysplasia on bone marrow aspirate / biopsy 10% dysplastic cells in any hematopoietic lineage

Ringed sideroblasts >15%

Presence of MDS defining cytogenetic abnormality

del(7q)

del(5q)

17q or t(17p)

del(13q)

del(11q)

del(12p) or t(12p)

del(9q)

idic(X)(q13)

t(11;16)

t(3;21)

t(1;3)

t(2;11)

inv(3)/t(3;3)

t(6;9)

--Note: As a sole cytogenetic abnormality in the absence of morphological criteria, gain of chromosome 8, del(20q) and loss of chromosome Y are not considered definitive evidence of MDS.

Alternate hematological diagnosis causing cytopenia

Pregnant at time of recruitment

Previous chemotherapy or radiotherapy"

=seymour=

[PoisonDwarf in reply to SeymourB]

Hi Seymour,

I'd be interested to know what they say when you do ask.

None of this is an option for me until treatment. As I have the SLL version & very little shows in my bloods with the exception of seemingly transient blips, so I have been very interested in the nodal & lymphoid tissue aspects of CLL.

From everything I've read on CHIP & CH plus all the linked variations, while the scientific body of knowledge has grown significantly, this has yet to result in a real world translation to clinical guidelines, particularly for the treatment naive.

As I understand it, a diagnosis of CLL/SLL itself could explain both cardio/vascular & bone density issues, in time maybe even elements of type II diabetes.

Despite the only palpable nodes being in my neck, CT tells a different story. My spleen is stable but my liver swells, I assume it clears house & returns to normal. At one point an RMT advised I needed to see my docs because of what he felt. I saw a GP at a walk in clinic he advised that my liver was swollen, he also felt something else but wasn't sure if it was my spleen but I needed a CT scan. I was waiting for a scan date as it was non-emergent. I saw a second RMT shortly after who refused to touch the area around the bottom of my ribs due to bruising and petechiae. He also suggested a CT scan. It was a short wait, however by the time the abdominal/pelvic scan was done my liver was back to normal & my ALT dropped from 36 to 12. It did show a new nodule (cyst?) on one of the superior kidney poles. All I got was a swift transfer to the ER & an extended wait time to ensure the contrast dye didn't send me into full blown anaphylaxis.

I also had a serum electrophoresis blood test. This showed that all my immune goblins (sic) were low. The lab recommended a repeat with urine electrophoresis. The second round of tests showed a notable drop in the gamma goblins (sic) plus a faint indeterminate spike. A further urine analysis ruled out Bence Jones proteins.

Are they linked or was it merely coincidental? My body says the former, but is silent on the causation or correlation. Is the root cause or driver some genetic mosaicism, given my family history? I really don't know, could just be I have a weird body. 🤣

[SeymourB in reply to PoisonDwarf]

PoisonDwarf -

I think the research on clonal hematopoiesis is too new to have any impact on CLL guidelines. The focus is still on MDS, AML, and CMML, and secondarily those malignancies after cytotoxic chemoimmunotherapy, and not natural aging CH.

I checked the current NCCN Guidelines, and the phrase clonal hematopoiesis, CHIP, clonal cytopenias of undetermined significance, or CCUS are not mentioned.

=seymour=

[PoisonDwarf in reply to SeymourB]

I agree with you. My interest was to find out about any possibility of MGUS which is the lymphoid MBL equivalent in the Myloid line.

My understanding, which could be incorrect of course is that NGS testing could establish.

The right panel & detailed enough genetic testing is the only way or as my Hematologist said we'd have to biopsy every node.

So unless M protein's appear definitely in my blood serum or urine, it's an academic exercise that's not going to happen in my case.

Time will tell.

[SeymourB in reply to PoisonDwarf]

PoisonDwarf -

And then if you DO have evidence of CHIP, what then? Does anyone want to treat it yet?

=seymour=

[PoisonDwarf in reply to SeymourB]

Precisely! How about yourself, what's your reasoning? What I came to understand about myself is that my brain needs to know possible outcomes. I have no control in either eventuality, but the ability to construct a rational narrative is key. Without the important pieces it behaves like a dog gnawing a bone. Conversely be it CHIP or CH, finding out if I have a pre-existing or potential myeloid clone makes for a quiet brain & dealing when needed.

I'm one who prefers to know, simple as. At one point my Dad was diagnosed with terminal lung cancer & I was advised to plan in short months not years. The very next day my Mum was diagnosed with vascular dementia. Practically it was a living hell involving a lot of tough conversations, heart breaking decisions & losing count of the number of times I flew the Atlantic. Nothing prepares you or cushions the shock when death happens, but I did a lot of my grieving in that period. I heard & said all that was needed, including my goodbyes. Sadly, my brother was unable to do that, his denial meant he paid a very steep price with complicated grief & his mental health.

Many won't understand, but that's OK, we all have our own ways of dealing.

Certainly I've always had a lot curiosity, & if you ever listened to my Mum I was born asking "why?". So I'm only half joking when I say it's likely curiosity will kill this cat. 😂

[SeymourB in reply to PoisonDwarf]

PoisonDwarf -

I'm a very intuitive person who can deal with a lot of possibilities if I can do it on my own schedule. Things like this fascinate me. I have no reason to expect the classic MDS CHIP, but I think CH is a natural process with aging, and I wonder how it's affected by CLL treatment. The more I read, the more I expect somatic mutations in many cell types, only some of which lead to cancer.

Beyond DNA changes, there are also epigenetic changes - little molecules added to DNA that change how it gets interpreted. We know so little about that as well. As time goes on, massively parallel sequencing of DNA and epigenetic markers will reveal a totally different world. Many of assumptions and dogma that we are forced to make due to lack of data, or from sampling only a single cell or a single human, will change. More biochemical modelling will be possible, and computers will process even more factors to come up with more accurate prognoses.

We already have prognoses for some diseases that can force us to face imminent death. Some people will prefer to not know. Medical records systems need to deal with that preference. They do not right now. I want to know, but I also want to know the range of doubt. There's always a range.

=seymour=

[PoisonDwarf in reply to SeymourB]

I certainly get that.

What truly fascinates me is the immune system. I believe & the science seems to support that all of this starts with our immune system. It's been estimated that it will still take another decade to decode the immune genome as it's of magnitudes more complex than the human genome.

Below is a brief introduction to the Human Immunome Project. There are different research initiatives as part of this cross country collaboration. The belief is that decoding the immune system is the real key to individualised medicine.

humanimmunomeproject.org/

[sunsetssr in reply to PoisonDwarf]

Thanks for sharing the website(humanimmunomeproject.org/). I encourage everyone interested to subscrib to recive updated information on this site.

[SeymourB in reply to PoisonDwarf]

PoisonDwarf -

I came across papers and videos regarding Immune Digital Twins, where various kinds of testing results are fed into computer models in an effort to better predict outcomes in diseases, including cancers.

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

Forum on immune digital twins: a meeting report

npj Systems Biology and Applications volume 10, Article number: 19 (2024)

The idea is to have a constantly updated model of a patient based on almost continuous testing through sensors, and adjustments to medications based on those measurements.

"A key point is that there is an ongoing exchange between the patient and the digital twin, with data from the patient used to dynamically recalibrate the digital twin, and predictions from the digital twin informing patient treatments. "

So much needs to be learned before this is possible, especially since immune function differs in different parts of the body. Blood tests alone are insufficient.

=seymour=

[PoisonDwarf in reply to SeymourB]

You're right of course. There are no quick or simple answers.

I read this in The Atlantic:

"There’s a joke about immunology. An immunologist and a cardiologist are kidnapped. The kidnappers threaten to shoot one of them, but promise to spare whoever has made the greater contribution to humanity. The cardiologist says, “Well, I’ve identified drugs that have saved the lives of millions of people.” Impressed, the kidnappers turn to the immunologist. “What have you done?” they ask. The immunologist says, “The thing is, the immune system is very complicated …” And the cardiologist says, “Just shoot me now.”

[SeymourB in reply to PoisonDwarf]

PoisonDwarf -

Love that joke. Most immunologists know it well.

That's from Ed Yong's "Immunology is where intuition goes to die."

theatlantic.com/health/arch... - Paywalled for some. A re-post can be found at - portside.org/2020-08-09/imm...

He also retells the immunologist and cardiologist joke.

=seymour=

[PoisonDwarf in reply to SeymourB]

🤣🤣🤣 Many a true word is spoken in jest.

Thanks for the chuckles.

[sunsetssr]

Thanks for excellent resources. My former Oncologist also mentioned that CH , most probably is age related but in the later visit she said "I'm less worried about blood cancer but mostly concerned about "CH" . This statement worried me more. I'd see a new Hematologist soon, and hopefully I'm empowered more by your resources, to get to the bottom of the issues. Thanks again for your time and the feedback. This group and all the administrative team are life safer in my humble openion.

[DriedSeaweed]

Dr. Ross Levine from MSK has nice discussions about CH on Youtube if you find a couple hours here and there to watch them.