Relationship between clone metrics and clinical outcome in clonal cytopenia

Gallì, Anna; Todisco, Gabriele; Catamo, Eulalia; Sala, Cinzia; Elena, Chiara; Pozzi, Sara; Bono, Elisa; Ferretti, Virginia Valeria; Rizzo, Ettore; Molteni, Elisabetta; Zibellini, Silvia; Sarchi, Martina; Boveri, Emanuela; Ferrari, Jacqueline; Fiorelli, Nicolas; Camaschella, Clara; Gasparini, Paolo; Toniolo, Daniela; Cazzola, Mario; Malcovati, Luca

doi:10.1182/blood.2021011323

Cited by 62 publications

(49 citation statements)

References 34 publications

(46 reference statements)

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“…The evidence of clonality in patients with otherwise unexplained cytopenia, impart a 17–27% risk of developing a subsequent myeloid neoplasm [ 9 – 11 ]. However, these studies did not assess the impact of prior DNA-damaging therapies, which is one of the strongest known risk factors for myeloid neoplasms [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…While studying t-MN patients, we encountered patients who had received DNA-damaging therapy and developed unexplained cytopenia with clonal abnormality, without morphological evidence of a myeloid neoplasm (i.e., CCUS). As a vast majority of patients in the CHIP, ICUS, or CCUS cohorts did not receive prior DNA-damaging therapies [ 2 , 9 – 11 ], the significance of CCUS following such therapies and its outcomes is not known. We hypothesized that clonal cytopenia following DNA-damaging therapy (therapy-related clonal cytopenia or t-CC) is a distinct entity from the WHO-defined t-MN.…”

Section: Introductionmentioning

confidence: 99%

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Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

et al. 2022

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Therapy-related myeloid neoplasms (t-MN) are aggressive leukemia that develops as a complication of prior exposure to DNA-damaging agents. Clonal cytopenia of undetermined significance (CCUS) is a precursor of de novo myeloid neoplasms. Characteristics of CCUS that develop following cytotoxic therapies (therapy-related clonal cytopenia, t-CC) and outcomes following t-CC have not been described. We identified 33 patients with t-CC and compared to a cohort of the WHO-defined t-MN (n = 309). t-CC had a distinct genetic and cytogenetic profile: pathogenic variants (PV) in TET2 and SRSF2 were enriched in t-CC, whereas TP53 PV was more common in t-MN. Ten (30%) t-CC patients developed a subsequent t-MN, with a cumulative incidence of 13%, 23%, and 50% at 6 months, 1, and 5 years, respectively. At t-MN progression, 44% of evaluable patients had identifiable clonal evolution. The median survival following t-CC was significantly superior compared all t-MN phenotype including t-MDS with <5% bone marrow blasts (124.5 vs. 16.3 months, P < 0.001) respectively. The presence of cytogenetic abnormality and the absence of variants in DNMT3A, TET2, or ASXL1 (DTA-genes) were associated with a higher likelihood of developing a subsequent t-MN and an inferior survival. We describe a putative precursor entity of t-MN with distinct features and outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

et al. 2022

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“…For specific mutational patterns involving mutations in splicing factor genes (e.g., SF3B1 , SRSF2 , or U2AF1 ) and/or multiple mutations, the progression risk of CCUS is ~20% per year [ 32 ]. Further studies confirmed the utility of specific mutational patterns and clonal metrics to define high-risk CCUS [ 34 ]. In contrast, the risk of progression is moderate if only a single mutation in the epigenetic modifier DNMT3A is observed [ 34 ].…”

Section: Chip and Hematologic Neoplasmsmentioning

confidence: 88%

“…Further studies confirmed the utility of specific mutational patterns and clonal metrics to define high-risk CCUS [ 34 ]. In contrast, the risk of progression is moderate if only a single mutation in the epigenetic modifier DNMT3A is observed [ 34 ]. In a study on persons aged ≥ 80 years, the clinical course of patients with high-risk CCUS was indistinguishable from that of overt myeloid neoplasms [ 35 ].…”

Section: Chip and Hematologic Neoplasmsmentioning

confidence: 88%

Clinical Significance of Clonal Hematopoiesis of Indeterminate Potential in Hematology and Cardiovascular Disease

Hoermann

2022

Diagnostics

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Liquid profiling uses circulating tumor DNA (ctDNA) for minimal invasive tumor mutational profiling from peripheral blood. The presence of somatic mutations in peripheral blood cells without further evidence of a hematologic neoplasm defines clonal hematopoiesis of indeterminate potential (CHIP). CHIP-mutations can be found in the cell-free DNA (cfDNA) of plasma, are a potential cause of false positive results in liquid profiling, and thus limit its usage in screening settings. Various strategies are in place to mitigate the effect of CHIP on the performance of ctDNA assays, but the detection of CHIP also represents a clinically significant incidental finding. The sequelae of CHIP comprise the risk of progression to a hematologic neoplasm including therapy-related myeloid neoplasms. While the hematological risk increases with the co-occurrence of unexplained blood count abnormalities, a number of non-hematologic diseases have independently been associated with CHIP. In particular, CHIP represents a major risk factor for cardiovascular disease such as atherosclerosis or heart failure. The management of CHIP requires an interdisciplinary setting and represents a new topic in the field of cardio-oncology. In the future, the information on CHIP may be taken into account for personalized therapy of cancer patients.

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“…Individuals with CCUS have a high probability of progression to hematologic malignancy, particularly MN, compared with individuals with cytopenias but no evidence of CH (5- and 10-year cumulative probability of progression: 82% vs. 9% and 95% vs. 9%, respectively) ( 49 ). Similar to CH, individuals with CCUS bearing only isolated DNMT3A mutations have a lower risk of progression to MN whereas individuals harboring TET2 , ASXL1 , TP53 , and spliceosome mutations have higher risks of MN ( 50 ).…”

Section: Mainmentioning

confidence: 99%

What Clonal Hematopoiesis Can Teach Us About MDS

2022

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Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Recent work has elucidated how the development and cellular fitness of CH is shaped by aging, environmental exposures, and the germline (inherited) genetic background of an individual. This in turn has provided valuable insights into the pathogenesis of MNs including MDS. Here, in this review, we discuss the genetic origins of CH, the environmental stressors that influence CH, and the implications of CH on health outcomes including MDS. Since MNs have shared risk factors and underlying biology, most of our discussion regarding the implications of CH surrounds MN in general rather than focusing specifically on MDS. We conclude with future directions and areas of investigation including how intervention studies of CH might inform future therapeutic approaches to MN including MDS.

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Relationship between clone metrics and clinical outcome in clonal cytopenia

Cited by 62 publications

References 34 publications

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

Clinical Significance of Clonal Hematopoiesis of Indeterminate Potential in Hematology and Cardiovascular Disease

What Clonal Hematopoiesis Can Teach Us About MDS

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