CHIP hematology - definition and characteristics

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of clonal molecular genetic or cytogenetic changes in blood or bone marrow cells in the absence of signs of hematological neoplasm and absence of cytopenia. The incidence of CHIP increases with age. While CHIP was detected only in rare cases in persons under 40 years of age, clonal hematopoiesis has been detected in about 10% of persons from the age of 70 onwards. Similar to patients with MGUS (monoclonal gammopathy of unclear significance) or with MBL (monoclonal B-cell lymphocytosis), individuals with CHIP showed an increased risk of developing hematological neoplasm. This risk was 11 to 13 times higher in individuals with clonal hematopoiesis, but the overall transformation rate was relatively low at 0.5-1% per year.

Classification of CHIP hematology

CHIP was introduced as a new term only a few years ago (Steensma et al. 2015). Through large studies of a total of more than 30,000 blood samples it could be shown that in some cases gene mutations exist in persons with inconspicuous blood counts, which had previously been detected mainly in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (Genovese et al. 2014, Jaiswal et al. 2014, Xie et al. 2014). The genes DNMT3A, TET2 and ASXL1 were most frequently affected.

Characteristics of CHIP (after Steensma et al. 2015)

  • Evidence of clonal hematopoiesis*
  • Absence of dysplasia of hematopoiesis in bone marrow
  • No proliferation of blasts in bone marrow/blood
  • Exclusion of paroxysmal nocturnal hemoglobinuria (PNH), MGUS and MBL
  • Progression rate of 0.5-1% per year

*somatic mutation with an allelic frequency of at least 2% in one of the genes: DNMT3A, TET2, JAK2, SF3B1, ASXL1, TP53, CBL, GNB1, BCOR, U2AF1, CREBBP, CUX1, SRSF2, MLL2 (KMT2D), SETD2, SETDB1, GNAS, PPM1D, BCORL1 or a non-disease-defining clonal cytogenetic alteration

Delineation from CCUS and MDS

In addition to CHIP, CCUS (clonal cytopenia of indeterminate significance), ICUS (idiopathic cytopenia of indeterminate significance) and IDUS (idiopathic dysplasia of indeterminate significance) are possible preliminary stages of MDS.

If clonal haematopoiesis is also accompanied by cytopenia, this is referred to as CCUS. CHIP and CCUS differ from ICUS and IDUS by the evidence of clonality. In IDUS, as in MDS, dysplasia is also present.

Table 1: Pre-MDS and MDS conditions: typical features and criteria, according to Valent et al. 2017

 

CHIP

CCUS

ICUS

IDUS

LR
MDS

HR
MDS

Monoclonal/Oligoclonal

+

+

-/+

+/-

+

+

Dysplasia*

-

-

-

+

+

+

Cytopenia(s)**

-

+

+

-

+

+

BM blasts

<5%

<5%

<5%

<5%

<5%

<20%

Flow abnormalities

+/-

+/-

+/-

+/-

++

+++

Cytogenetic abnormalities

+/-

-

+/-

+/-

+

++

Molecular aberration/s

+

+

-

-

++

+++

*At least 10% of all cells in a given lineage (erythroid, neutrophil, or megakaryocyte) are dysplastic.

**Persistent cytopenia(s) recorded over a time-period of at least 4 months.

CHIP hematology - Diagnostics

Cytomorphology

If clonal hematopoiesis is present due to the molecular genetic or cytogenetic findings, CHIP hematology (absence of dysplasia and cytopenia) should be distinguished from CCUS (cytopenia, but absence of dysplasia) or myeloid neoplasia in a cytomorphological examination.

Chromosome analysis

Clonal hematopoiesis can also be diagnosed in the absence of somatic mutations due to non-disease-defining clonal cytogenetic changes.

FISH

If it is not possible to perform a chromosome analysis, FISH can also be used to detect clonal haematopoiesis.

Molecular genetics

Difficult to differentiate CHIP vs. MDS

The sole detection of a mutation in one of the genes frequently mutated in AML and MDS does not allow a distinction to be made between CHIP and MDS (see also Diagnostics MDS (molecular genetics)). A smooth transition between CHIP and MDS is assumed to be probable. An important indication of this is the increase in genetic complexity (see Table 2) with regard to the number of mutations as well as clone size (allele frequency) (Cargo et al. 2015, Bejar 2017, Malcovati et al. 2017, Bewersdorf et al. 2019).

Table 2: Comparison of genetic characteristics between CHIP, CCUS and MDS, according to Bejar 2017

 CHIP (unselected population)CCUS (at diagnosis)MDS (all risk groups)
Commonly mutated genesDNMT3A, TET2, ASXL1, PPM1D, JAK2, TP53TET2, DNMT3A, ASXL1, SRSF2, TP53SF3B1, TET2, ASXL1, SRSF2, DNMT3A
Mean # of Mutations~1~1,6~2,6
Typical VAF9-12%30-40%30-50%
Incidenceabout 10-15% of 70 year-oldsabout 35% of ICUSmay be <50% of cytopenic patients

Overall, MDS are molecularly more complex than CHIP: there are usually two or more mutations and the mutation load is usually above 10% (Haferlach et al. 2014, Malcovati et al. 2017, Sperling et al. 2017). In addition, mutations in certain genes (e.g. spliceosome factors) are found more frequently in MDS than in CHIP, see Table 2 (Bejar 2017). Since a progression (usually into MDS or AML, more rarely into myeloproliferative or lymphatic neoplasm) leads to an accumulation of several mutations (e.g. Steensma et al. 2015), it is recommended to perform follow-up examinations in questionable cases.

Table 3: Somatically mutated genes detectable in patients with MDS and CHIP (Valent et al. 2017)

Table 3 shows an overview of known mutations in MDS and CHIP. The presence of multiple mutations (e.g. SF3B1, SRSF2) increases the probability of an MDS diagnosis or that the patient will develop MDS.

Gene

Chromosome localisation

Frequency*

MDS

CHIP

NRAS

1p13.2

+/-

-

DNMT3A

2p23
 

+

+

SF3B1

2q33.1
 

+

+/-

IDH1

2q33.3
 

+/-

-

GATA2

3q21.3

-

-

KIT

4q11-12
 

+/-

-

TET2

4q24
 

+

+

NPM1

5q35.1
 

-

-

EZH2

7q35-36

+/-

-

JAK2

9p24

+/-

+

CBL

11q23.3

+/-

+/-

KRAS

12p12-11
 

-

-

ETV6

12p13
 

-

-

FLT3

13q12
 

-

-

IDH2

15q26.1
 

-

-

TP53

17p13.1

+/-

+/-

PRPF8

17p13.3

-

-

SRSF2

17q25.1
 

+

+/-

CEBPA

19q13.1
 

-

-

ASXL1

20q11
 

+

+

U2AF1

21q22.31
 

+/-

-

RUNX1

21q22.12
 

+/-

-

BCOR

Xp11.4

-

-

ZRSR2

Xp22.1
 

+/-

-

STAG2

Xq25

+/-

-

*Score of frequency:

-             <1%     of all patients

+/-         1-10% of all patients

+            >10%  of all patients

Prognosis of CHIP hematology

Association between CHIP and hematological and cardiovascular diseases

Total exome sequencing (i.e. sequencing of all protein-coding genes) of more than 17,000 DNA samples from peripheral blood not selected for hematological diseases showed that age-related clonal hematopoiesis is associated with an increased risk of developing hematological neoplasm (Jaiswal et al. 2014).

Jaiswal and colleagues also found an association between CHIP hematology and increased mortality (Jaiswal et al. 2014), which, according to current knowledge, is due to an association between CHIP and cardiovascular diseases (Jaiswal et al. 2014 & 2017). Especially in the case of TET2 mutations there are indications that faulty inflammatory reactions could be the cause (Jaiswal et al. 2017).

CHIP-associated mutations and mutation patterns differ in their predictive value for a progression into MDS or AML

The possible progression of clonal hematopoiesis into MDS was investigated in a large international study for patients with unexplained cytopenia of undetermined significance (CUS). The data provide first indications that the detection of mutations has a predictive value in this context. Patients in whom a mutation was detected had an approximately 14-fold increased risk of developing myeloid neoplasm. The occurring mutations or mutation patterns had different effects on the risk of progression. For patients with a mutation in one of the spliceosome genes (SF3B1, SRSF2, U2AF1, ZRSR2) or in one of the epigenetic factors TET2, ASXL1 or DNMT3A in combination with another mutation, the risk was about 20% per year. In patients with a different mutation pattern, the risk was approximately 10% per year (Malcovati et al. 2017) (see also CCUS).

In two retrospective studies it was evaluated whether risk factors for the development of AML can be identified. Especially mutations in TP53, IDH1/2 and spliceosome genes were associated with an increased risk of progression. Just as for a possible progression into MDS (see CHIP (molecular genetics)), an influence of clone size, the number of mutations as well as the kinetics of clonal expansion could be determined (Abelson et al. 2018, Desai et al. 2018).

CHIP hematology as a possible risk factor for the development of therapy-associated myeloid neoplasm

CHIP hematology clones can gain and expand a selective survival advantage under haematological stress, which can result from cytotoxic therapy, radiation or stem cell transplantation (Ortmann et al. 2019, Coombs et al. 2017, Wong et al. 2018). In particular, TP53 and PPM1D mutant clones are associated with the development of therapy-associated neoplasms after cytotoxic therapy (Coombs et al. 2017, Hsu et al. 2018, Kahn et al. 2018, Wong et al. 2015 & 2018). Mutations of these two genes are found with a frequency of 4% each among the CHIP-associated mutations (Heuser et al. 2016).

Identification of CHIP possibly of future importance for stem cell transplantation

In a retrospective analysis, it was shown that patients with CHIP (CHIP hematology) after autologous stem cell transplantation for the treatment of lymphoma had an increased risk of developing therapy-associated myeloid neoplasm. Furthermore, overall survival was significantly reduced (Gibson et al. 2017).

However, in a first study of allogeneic stem cell transplantation, the CHIP hematology status of the donor did not affect the overall survival of the recipients (Frick et al. 2018). In the context of CHIP-positive stem cell donors, an increased incidence of chronic graft-versus-host disease was observed, which was associated with a lower rate of recurrence or progression (Frick et al. 2018). However, there are case reports on the occurrence of donor cell leukemia after allogeneic stem cell transplantation in connection with CHIP-positive older donors (Gondek et al. 2016, Frick et al. 2018).

CHIP hematology: Recommendation

Also in view of the lack of possibilities for therapeutic intervention, screening for the presence of a CHIP hematology is not recommended in persons with normal blood counts (Heuser et al. 2016). Often the detection of clonal haematopoiesis is a random finding. With a normal blood count, a differential blood count should be performed at regular intervals (initially after 3 months, later every 12 months) in patients with CHIP hematology in order to detect possible progression. If the patient has peripheral cytopenia, a bone marrow puncture and a differential blood count are recommended initially after 1, 2 and 3 months and subsequently every 3 months (Heuser et al. 2016).

References

Abelson S et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 2018;559:400-404.

Bejar R. Implications of molecular genetic diversity in MDS. Curr Opin Hematol. 2017;24(2):73–78.

Bewersdorf JP et al. From clonal hematopoiesis to myeloid leukemia and what happens in
between: Will improved understanding lead to new therapeutic and preventive opportunities? Blood Reviews 2019;37:100587.

Cargo CA et al. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood 2015;126(21):2362–2365.

Coombs CC et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 2017;21:374-382.

Desai P et al. Somatic Mutations Precede Acute Myeloid Leukemia Years Before Diagnosis. Nature Medicine 2018; 24(7),1015-1023.

Dorsheimer L et al. Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure. JAMA Cardiol. 2019;4(1):25-33.

Frick M et al. Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation. JCO 2019;37(5):375-385.

Genovese G et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. NEJM 2014;371(26):2477-2487.

Gibson CJ et al. Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol 2017;35(14):1598-1605.

Gondek LP et al. Donor cell leukemia arising from clonal hematopoiesis after bone marrow transplantation. Leukemia 2016;30(9):1916-1920.

Haferlach T et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014;28(2):241-247.

Heuser M et al. Clonal Hematopoiesis of Indeterminate Potential. Dtsch Arztebl Int 2016;113(18):317-322.

Hsu JI et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 2018;23:700-713.

Jaiswal S et al. Age-related clonal hematopoiesis associated with adverse outcomes. NEJM 2014;371(26):2488-2498.

Jaiswal S et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. NEJM 2017;377:111-121.

Kahn JD et al. PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 2018;132:1095-1105.

Malcovati L et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 2017;129(25):3371-3378.

Mas-Peiro S et al. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. European Heart Journal 2019;ehz591.

Ortmann CA et al. Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation. Cell Reports 2019;27(7):2022-2028.e3.

Sperling AS et al. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer 2017;17(1):5-19.

Steensma DP et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015 Jul 2;126(1):9-16.

Valent P et al. Proposed Minimal Diagnostic Criteria for Myelodysplastic Syndromes (MDS) and Potential pre-MDS Conditions. Oncotarget 2017;8(43):73483-73500.

Wong TN et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 2015;518:552-555.

Wong TN et al. Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun 2018;9(1):455.

Xie M et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014;20(12):1472-1478.