We identified references for this Viewpoint through searches of PubMed databases and abstracts of the American Society for Hematology and the American Society of Clinical Oncology, using the search terms “CHIP”, “CCUS”, “ICUS”, and “clonal haematopoiesis”. We included articles that were published from Jan 1, 2010, to August 1, 2019. We considered results from all papers published in English only when drafting the manuscript, but included what we currently view as many of the most seminal papers
ViewpointAssessing clonal haematopoiesis: clinical burdens and benefits of diagnosing myelodysplastic syndrome precursor states
Introduction
A patient who presents to the clinic for investigation of peripheral blood cytopenia brings dilemmas of diagnosis, monitoring, and therapy. Refractory cytopenia in the context of a normocellular or hypercellular bone marrow can often raise concern for myelodysplastic syndromes and related disorders.1, 2 Myelodysplastic syndrome encompasses a heterogeneous collection of clonal haematopoietic malignancies affecting a predominantly older population. The disorder is characterised by poor overall survival due to ineffective haematopoiesis, progressive cytopenia, and transformation to acute myeloid leukemia.3 Extremely rare in patients younger than 50 years, the prevalence of myelodysplastic syndrome increases with age. Between 30 000 and 40 000 cases are diagnosed per year,4 with a median age at diagnosis of about 70 years.5 The diagnosis of myelodysplastic syndrome has become more complex since myelodysplastic syndrome precursor states and other causes of unexplained cytopenias have been defined. The advent of next-generation sequencing technology has provided additional diagnostic information, which could allow important clinical insights, such as early identification of predisposition states to myelodysplastic syndrome and increased accuracy in diagnosis of myelodysplastic syndrome.6, 7 However, this added ability to assess a patient for evidence of clonal haematopoiesis poses inherent challenges of how to allow these results to affect the patient's health—both physical and emotional.
Patients with unexplained cytopenias are increasingly undergoing molecular testing by next-generation sequencing of peripheral blood or bone marrow to diagnose possible myelodysplastic syndrome precursor states. These tests can detect mutations in individuals without morphological or cytogenetic evidence of myeloid neoplasm or myelodysplastic syndrome, and new entities have therefore been defined to categorise these patients appropriately. Some of these precursor states could evolve to frank malignancy, making it important to define a path that explains these conditions and allows proper understanding of and context for a patient's health.5, 8, 9
Section snippets
Genesis and evolution of clonal haematopoiesis
Clinicians need to understand the biological explanation of positive next-generation sequencing results to guide their next steps, and patients also deserve and often require explanations to contextualise their new diagnosis. In truth, the acquisition of somatic mutations is an unavoidable consequence of cell division. Even though fewer than three somatic mutations occur per cell division, mutations can accumulate quickly in rapidly dividing haematopoietic progenitor pools.10, 11, 12, 13 The
Assessment of clonality for CHIP
It is now widely accepted that cancers arise from a single progeny, as a result of uncontrolled growth of its daughter cells or clones. The clonal nature of cancer was first described in the 1960s using X-chromosome inactivation studies.19, 20 Most contemporary methods of clonality detection are based on genetic analysis and include gene rearrangements (T-cell and B-cell receptors), structural and numerical chromosomal changes, small copy number variants, and somatic point mutations. All these
Definition of clonal haematopoiesis
Unfortunately, the term clonal haematopoiesis, outside its undisputable association with haematological malignancies, misses a degree of precision in its application. Clonal haematopoiesis is frequently defined as non-reactive, relative expansion of haematopoietic clones—regardless of magnitude—detected by any means and at any point in time. Although this definition could allow potential categorisation for some patients, the defining characteristics of clinically relevant clonal haematopoiesis
Assessment of clonality in diagnosis
Since the first systematic reports in the late 1970s, numerical and structural chromosomal abnormalities and the use of various cytogenetic techniques have remained central to diagnostic testing, risk stratification, and therapeutic decision making. Beginning in 2001 (in recognition of chromosome 5q deletion syndrome), and then more broadly in 2007, WHO classification recognised cytogenetics as an essential diagnostic tool.3 The diagnosis of some types of acute myeloid leukaemia with recurrent
Diagnostic handling of CHIP
As with any new evolution in clinical classification systems, inherent limitations become apparent. It is in this way that clinicians must fully comprehend the consequences of labelling patients with precursor states. The prospective Myelodysplastic Syndrome Natural History Study40 is currently enrolling patients with ICUS to address this very issue. Although underdiagnosis might not be a relevant problem because disease will declare itself with time, overdiagnosis can be anxiety provoking in
Malignant consequences of CHIP
With regards to the risk of malignant consequences, CHIP can apply the multiple hit theory in cancer evolution.45 People with CHIP generally have a single somatic mutation and do not have an overt malignancy. The mutations found in people with CHIP are also common in myeloid malignancies, including acute myeloid leukaemia, myelodysplastic syndrome, myeloproliferative neoplasms, and some lymphomas.46 In most cases, transformation to malignancy requires the sequential acquisition of multiple
CHIP at the bedside
Providers of clinical care value the capacity to contextualise disease manifestations (and the patients they affect) into categories to help to create a path forward. The aforementioned aid this goal and have the added use of predicting with greater accuracy which patients might develop myeloid neoplasms.7 Additionally, these entities in many ways justify the use of next-generation sequencing at diagnosis. This form of molecular genetic testing promotes and confirms the diagnosis of a clonal
Conclusions
Clonal haematopoiesis is an exciting area of research, leading to better knowledge and further diagnosis of precursor status for patients. However, comprehension of clonal haematopoiesis is ongoing, and as yet, we sometimes struggle to interpret clonal haematopoiesis results with complete diagnostic and prognostic certainty. When faced with uncertainty, some patients and providers will be content to let events unfold beyond their control. However, other patients (or physicians) might feel
Search strategy and selection criteria
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Cited by (45)
Review of clonal hematopoiesis, subtypes and its role in neoplasia and different morbidities
2023, Leukemia ResearchAcute myeloid leukaemia
2023, The LancetClonal hematopoiesis and cardiovascular diseases: role of JAK2V617F
2023, Journal of CardiologyCitation Excerpt :Together, management for cardiovascular diseases in persons with JAK2V617F-CH and MPN patients is critical for improving their prognosis. VAF is defined by the percentage of mutated DNA molecules relative to total DNA input [48]. In cancer-associated somatic mutations, given that one allele (heterozygous) is mostly affected, a VAF of 50% implies that 100% of tumor cells carry the somatic mutations [48].