CHIP in hematology (clonal hematopoiesis of indeterminate potential)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory*
  • Method:
    Immunophenotyping
  • Anticoagulant:
  • Recommendation:
    no
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

*if molecular genetics is positive

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

Low risk
MDS

High risk
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

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).

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