Episode 115: AML Series, Pt. 1 - CHIP, CCUS, ICUS, oh my!
This week, we kick off a new series focusing on myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this first episode, we discuss the alphabet soup of premalignant hematologic conditions including CHIP, CCUS, and ICUS, before moving onto MDS and AML in future episodes.
What is the approach to a patient with cytopenias?
Always establish a timeline for the cytopenias and look at older labs
Look at the differential and ensure there are no atypical cells that could represent leukemic blasts
If the patient has a macrocytic anemia and another cytopenia, start with reversible causes (e.g. nutritional deficiencies) but keep primary bone marrow malignancy or clonal mutation on the differential diagnosis
With multiple cytopenias, always consider nutritional deficiencies of B12, folate, and copper.
In particular, copper deficiency should be considered in patients with history of gastric bypass
Copper deficiency can mimic myelodysplastic syndrome (more on this in future episodes!)
After that, go with the Fellow On Call mantra of infections, medications, and toxins
Rule out viral infections: HIV, hepatitis B, hepatitis C, EBV, CMV
Take a good medication history to ensure the cytopenia(s) did not coincide with a recent medication change
Common medications that can cause macrocytosis include antiretrovirals and hydroxyurea
Chronic alcohol use leads to a macrocytic anemia with thrombocytopenia but remember that other recreational drugs can also lead to cytopenias
Evaluation for liver disease is also important as patients with cirrhosis and splenomegaly can have cytopenias in all three lines
After completing non-malignant workup, then it is important to consider a bone marrow biopsy to rule out a primary bone marrow malignancy
This is especially true when considering a patient with macrocytic anemia and another cytopenia
Regarding the small IgG M-spike: Check out the Intro to MGUS episode!
What is the mechanism of hematopoiesis?
The bone marrow has a self-renewing population of stem cells that differentiate into multipotent hematopoietic progenitor stem cells
This multipotent hematopoietic stem cell becomes one of two things:
Common lymphoid progenitor stem cell → B and T cells
Common myeloid progenitor stem cell → everything else! (neutrophils, eosinophils, basophils, monocytes, red cells, and platelets)
The lymphoid and myeloid progenitor stem cells undergo several maturation steps to become a mature cell
All of these maturation steps requires DNA replication
Over time, it is natural for a mistake to occur during repeated DNA replication, resulting in a mutation that is missed by normal DNA repair mechanisms
The diversity of stem cells protects us from natural somatic mutations that occur with aging and repeated DNA replication
Often, mutations occur in the common myeloid progenitor stem cell and therefore will be found in downstream mature neutrophils, monocytes, etc.
Image source: https://en.wikipedia.org/wiki/Haematopoiesis#/media/File:Hematopoiesis_simple.svg. No copyright infringement intended.
What is clonality?
Clonality is defined by a group of identical cells that are derived from the same cell
When a mutation occurring in a progenitor cell is results in the same mutation found in many successor cells, it is called clonal hematopoiesis - but the clone size is not always large and may go unnoticed because of the significant stem cell diversity
This will not lead to a laboratory abnormality such as macrocytosis until there is enough clonal expansion to lead to a significant contribution from these mutated stem cells to blood cell production as compared to normal hematopoietic stem cells
There are over 100,000 hematopoietic stem cells contributing to blood cell production – therefore, a single cell with a mutation has to clonally expand to a significant degree before changes are noted
There are two alleles for each gene and mutations are often heterozygous (i.e. patients have one affected allele and one unaffected allele)
What is the origin of clonal hematopoiesis of “indeterminate potential”?
There were several historical studies that led to the concept that cancers arise from multiple somatic mutations occurring at different times
One pivotal paper, published in Science in 1976, described the concept of how one mutation could lead to genetic instability and the development of subsequent mutations leading to cancer
In the 2000s, DNA sequencing became more widely available and it was found that mutations in hematopoietic stem cells disrupting normal hematopoietic stem cell population dynamics likely preceded the development of a variety of hematologic malignancies – including MDS and AML
In patients with leukemia who were treated and achieved remission, a few pivotal studies showed persistence of mutations in stem cells found in prior leukemic cancer cells
These stem cells survived chemotherapy and ultimately led to development of novel mutations and subsequent cancer relapse
This solidified the idea that there was likely a clonal expansion of stem cells prior to the development of the underlying leukemia
In 2014, one of the first large scale population studies for clonal hematopoiesis was published in NEJM
Whole exome DNA sequencing was performed on the peripheral blood of 12,380 Swedish people from a registry that was designed to identify genetic mutations associated with psychiatric disorders like schizophrenia
Clonal hematopoiesis with somatic mutations occurred in 10% of people above the age of 65 and only in 1% of those younger than age 50
The most common mutations were DNMT3A, ASXL1, and TET2 – also commonly found in hematologic malignancies
The risk of developing a hematologic malignancy with clonal hematopoiesis was low, about 1% per year (similar to MGUS development into multiple myeloma)
In a multivariate survival analysis, the hazard ratio for developing a hematologic malignancy for those with clonal hematopoiesis vs. those without was 12.9
However, the absolute event rate was only 0.04% in patients with clonal hematopoiesis
It is important to remember that the overall rate of malignancy in patients with clonal hematopoiesis remains quite low!
A subsequent paper in Blood published in 2015 defined the term CHIP because these patients had a low risk of progression to overt malignancy, as with MGUS or monoclonal B cell lymphocytosis
Another study published in NEJM in 2017 identified that these patients have a two fold increased risk for cardiovascular disease and overall mortality – but we still don’t know exactly how to intervene early in this patient population
One paper published in Nature in 2023 showed that clonal hematopoiesis was associated with protection from Alzheimer’s disease!
What is the formal definition of clonal hematopoiesis of indeterminate potential (CHIP)?
One formal definition of CHIP is having a leukemia associated gene mutation with a variant allele frequency of greater than or equal to 2%, normal peripheral blood counts, and no diagnosis of another hematologic malignancy
Long standing unexplained macrocytosis without cytopenias can be concerning for CHIP
What is variant allele frequency (VAF)?
VAF is the ratio of mutated alleles to normal alleles
If each cell has two alleles and a patient inherited a mutated allele from one parent and a normal allele from the other parent, we would see a VAF of 50% because the mutated allele would be present in every cell
With regards to hematopoietic cells with mutations, not every cell will have the mutation because of the significant amount of stem cell diversity
There might be clonal expansion of a mutated cell with a heterozygous mutation in one of the two alleles – but this would not represent the entire population
If 20% of the cells in the marrow have a mutated allele, then the variant allele frequency would be 10%
Out of every 100 cells, 80 cells would have no mutation and 20 cells would have a mutation
Since there are two alleles per gene in each cell, there would be 160 normal alleles in the 80 cells without a mutation and 20 mutated alleles in the 20 cells with a heterozygous mutation
The ratio would be 20 divided by 180 which is roughly 10%, so the VAF would be 10%
The actual computation for the VAF is extremely complicated and doesn’t always follow a perfect rule – things like cellularity, copy number changes, and loss of heterozygosity can affect this number
Trending a VAF for treatment response can be very complicated and should always be done in consultation with a pathologist
What VAF corresponds to a germline mutation?
Ideally, a germline mutation would have a VAF of 50% but in general it’s important to think about a germline mutation when the VAF is > 35%
This also means that a patient with AML or MDS with a mutation that has a higher VAF is more likely to be the founder mutation, while the lower VAF mutations are more likely subclones
There is divergent branching evolution in these heterogeneous disease states
What is the significance of VAF with regards to CHIP?
For CHIP, a VAF >20% means that the clone has expanded significantly more than normal and portends a higher risk (more shortly!)
Should bone marrow or peripheral blood be assessed when looking for CHIP?
There is no difference in general diagnosis because this mutation occurred in an early progenitor myeloid stem cell so all the mature cells would have the mutation and these can be found in the peripheral blood
The main difference might be in the sensitivity of the VAF percentage
What about a VAF less than two percent?
If there is a VAF less than 2% for a mutation, it is termed “age related clonal hematopoiesis” – these are common in the older population
What is clonal cytopenia of undetermined significance (CCUS)?
Essentially, CCUS is CHIP with one or more cytopenias
It is termed “undetermined significance” because not every patient will develop a hematologic malignancy
Must rule out an underlying hematologic malignancy with a bone marrow biopsy
Why should next generation sequencing (NGS) not be performed on every patient with cytopenias?
Other causes are much more common
Universal NGS testing will result in overdiagnosis and unnecessary patient anxiety
There is no evidence that this will change quality of life or overall survival
An appropriate plan is serial CBC monitoring and performing bone marrow biopsy if cytopenias worsen or symptoms develop
What is the natural history of CCUS?
Like CHIP, not all patients with CCUS will go on to develop a hematologic malignancy
They will often follow one of three courses:
#1: The cytopenia(s) spontaneously resolves with time
#2: The cytopenia(s) persists over many years but never causes symptoms
#3: The patient develops a hematologic malignancy – remember that this is a relatively uncommon occurrence!
Is there any data for risk stratification of CHIP and CCUS?
Some patients may get a coronary artery calcium score if they have a CHIP mutation given the twofold risk of cardiovascular disease
However, there is no evidence on how to manage these patients or the role of aspirin or statin therapy
There were several large database studies that attempted to identify risk factors for progression to a myeloid malignancy
Findings from those studies showed that multiple mutations, splicing factor mutations, and higher VAFs were risk factors for progression
A study published in NEJM Evidence 2023 created a risk score for these patients
The study included nearly 440,000 healthy patients from the UK Biobank with information on development of myeloid malignancies
Risk factors were identified in multivariate analysis while controlling for sex, smoking status, and history of cancer
The following risk factors were included in a risk calculator:
Higher Risk Mutations
Splicing factor mutations (SRSF2, SF3B1, and ZRSR2)
TP53 mutation
AML related mutations (e.g. IDH and FLT3)
VAF greater than or equal to 20%
MCV over 100
RDW greater than 15%
Presence of CCUS
One lower risk factor identified was the presence of a single DNMT3A mutation
Calculator: http://www.chrsapp.com/
The calculator stratifies patients into low risk, intermediate risk, or high risk
About 90% of patients will generally be low risk, 9% will be intermediate risk, and only 1% will be high risk
Patients with high risk CHIP or CCUS had a ~40-50% absolute risk of developing a myeloid neoplasm over the next 10 years
Those with intermediate had a ~8% risk at 10 years
Those with low risk had a 0.6% risk at 10 years
For patients with high risk CCUS, it would be reasonable to check CBC every 3-6 months to ensure lack of progression and monitor need for bone marrow biopsy
There are no guidelines regarding this!
Some patients may be candidates for clinical trials but it is important to have the discussion of high risk for overtreatment
Repeat NGS testing may not be useful and should only be done for research purposes
What is idiopathic cytopenia of undetermined significance (ICUS)?
ICUS would describe a patient with one or more cytopenia(s) with no identifiable mutation
There is no good way to risk stratify these patients
Their blood counts should be observed while ruling out other more common etiologies.
These patients often have lifelong low blood counts but have a low chance to develop a malignancy.
References:
https://www.nature.com/articles/s41586-018-0497-0
https://pubmed.ncbi.nlm.nih.gov/959840/: 1976 Science publication that established the idea of clonality driving malignancy
https://www.nature.com/articles/nature13038
https://www.nejm.org/doi/full/10.1056/NEJMoa1409405: 2014 NEJM paper evaluating clonal hematopoeisis
https://ashpublications.org/blood/article/126/1/9/34336/Clonal-hematopoiesis-of-indeterminate-potential: Blood article that defined the concept of CHIP
https://www.nejm.org/doi/full/10.1056/NEJMoa1701719: 2017 NEJM article establishing the connection between CHIP and cardiac disease
https://www.nature.com/articles/s41591-023-02397-2: 2023 Nature publication showing connection to Alzheimer’s disease
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Neil Biswas
Social media management: Ronak Mistry
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