Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation

Ortmann, Christina A.; Dorsheimer, Lena; Abou-El-Ardat, Khalil; Hoffrichter, Jennifer; Aßmus, Birgit; Bönig, Halvard; Scholz, Anica; Pfeifer, Heike; Martin, Hans; Schmid, Tobias; Brüne, Bernhard; Scheich, Sebastian; Steffen, Björn; Riemann, Julia; Hermann, Scott; Dukat, Alexandra; Bug, Gesine; Brandts, Christian; Wagner, Sebastian; Serve, Hubert; Rieger, Michael A.

doi:10.1016/j.celrep.2019.04.064

Cited by 52 publications

(43 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, this research may also be important for informing HCT survivors and their caregivers as they consider plans for long-term surveillance and follow-up. A recent study of 81 patients undergoing autologous HCT found that CH mutations present before HCT were more likely to dominate blood reconstitution over wild-type hematopoietic stem cells after HCT [21], leading to an increased future risk of CH-associated complications in survivors. Therefore, information on CH status (either before or after HCT) may allow for implementation of more frequent screening intervals and management of modifiable risk factors in at-risk individuals.…”

Section: Discussionmentioning

confidence: 99%

Association between Clonal Hematopoiesis and Late Nonrelapse Mortality after Autologous Hematopoietic Cell Transplantation

Slavin

Teh

Weitzel

et al. 2019

Biology of Blood and Marrow Transplantation

View full text Add to dashboard Cite

Clonal hematopoiesis (CH), characterized by the accumulation of acquired somatic mutations in the blood, is associated with an elevated risk of aging-related diseases and premature mortality in non-cancer populations. Patients who undergo autologous hematopoietic cell transplantation (HCT) are also at high risk of premature onset of aging-related conditions. Therefore, we examined the association between pretreatment CH and late-occurring (1 year) nonrelapse mortality (NRM) after HCT. We evaluated pathogenic and likely pathogenic CH variants (PVs) in 10 patients who developed NRM after HCT and in 29 HCT recipient controls matched by age at HCT § 2 years (median, 64.6 years; range, 38.5 to 74.7 years), sex (79.5% male), diagnosis (61.5% with non-Hodgkin lymphoma, 18.0% with Hodgkin lymphoma, and 20.5% with multiple myeloma), and duration of follow-up. We analyzed mobilized hematopoietic stem cell DNA in samples collected before HCT using a custom panel of amplicons covering the coding exons of 79 myeloid-related genes associated with CH. PVs with allele fractions >2% were used for analyses. Cases were significantly more likely than controls to have CH (70% versus 24.1%; P = .002), to have 2 unique PVs (60% versus 6.9%; P < .001), and to have PVs with allelic fractions 10% (40% versus 3.4%; P = .003). Here we provide preliminary evidence of an association between pre-HCT CH and NRM after HCT independent of chronologic age. Integration of CH analyses may improve the accuracy of existing pre-HCT risk prediction models, setting the stage for personalized risk assessment strategies and targeted treatments to optimally prevent or manage late complications associated with HCT.

show abstract

Section: Discussionmentioning

confidence: 99%

Association between Clonal Hematopoiesis and Late Nonrelapse Mortality after Autologous Hematopoietic Cell Transplantation

Slavin

Teh

Weitzel

et al. 2019

Biology of Blood and Marrow Transplantation

View full text Add to dashboard Cite

show abstract

“…CHIP may contribute to altered transplant outcomes and the development of DDL after both autologous and allogeneic HSCT ( Table 1 ). Autologous transplantation can facilitate expansion of HSPC clones containing CHIP-associated mutations ( Ortmann et al., 2019 ). These HSPCs demonstrate long-term engraftment and reconstitute the blood cell lineages.…”

Section: Main Textmentioning

confidence: 99%

“…CHIP patients exhibited longer neutrophil reconstitution, longer periods of hospitalization, and prolonged neutropenia. Clones carrying these preleukemic mutations can be detected years before disease onset and expand in response to transplantation ( Berger et al., 2018 ; Ortmann et al., 2019 ). The stress of transplantation has been proposed to drive expansion of HSPCs containing CHIP-associated mutations, implicating factors in the transplant environment in the modulation of HSPCs containing CHIP-associated mutations ( Ortmann et al., 2019 ).…”

Section: Main Textmentioning

confidence: 99%

“…Clones carrying these preleukemic mutations can be detected years before disease onset and expand in response to transplantation ( Berger et al., 2018 ; Ortmann et al., 2019 ). The stress of transplantation has been proposed to drive expansion of HSPCs containing CHIP-associated mutations, implicating factors in the transplant environment in the modulation of HSPCs containing CHIP-associated mutations ( Ortmann et al., 2019 ). In patients who underwent autologous transplantation for lymphoma, CHIP correlated with inferior survival and an increased risk of therapy-related myeloid neoplasms (TMNs) ( Gibson et al, 2017b ).…”

Section: Main Textmentioning

confidence: 99%

See 1 more Smart Citation

Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia

Burns

Kapur

2020

Stem Cell Reports

View full text Add to dashboard Cite

Hematopoietic stem cell transplantation (HSCT) is a critical treatment modality for many hematological and non-hematological diseases that is being extended to treat older individuals. However, recent studies show that clonal hematopoiesis of indeterminate potential (CHIP), a common, asymptomatic condition characterized by the expansion of age-acquired somatic mutations in blood cell lineages, may be a risk factor for the development of donor-derived leukemia (DDL), unexplained cytopenias, and chronic graft-versus-host disease. CHIP may contribute to the pathogenesis of these significant transplant complications via various cell-autonomous and non-cell-autonomous mechanisms, and the clinical presentation of DDL may be broader than anticipated. A more comprehensive understanding of the contributions of CHIP to DDL may have important implications for the screening of donors and will improve the safety of HSCT. The objective of this review is to discuss studies linking DDL and CHIP and to explore potential mechanisms by which CHIP may contribute to DDL.

show abstract

“…[11][12][13][14][15][16] Moreover, in patients with CH, highdose conditioning regimens as part of treatment with ASCT have been shown to provide a proliferative advantage for mutated cell clones. 17 The impact of individual mutations in malignant transformation is still being investigated. However, it has become evident that mutations in both DNMT3A and TET2 can be detected in a large fraction of the healthy adult population 18 ; individually, these clones often display little to no clonal evolution over time and are associated with a lower increase in risk of developing myeloid neoplasms compared with mutations in TP53, IDH1/2, and spliceosome genes.…”

Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post–autologous stem cell transplantation

Soerensen¹,

Aggerholm²,

Kerndrup

et al. 2020

Blood Advances

View full text Add to dashboard Cite

Therapy-related myeloid neoplasms (tMN) develop after exposure to cytotoxic and radiation therapy, and due to their adverse prognosis, it is of paramount interest to identify patients at high risk. The presence of clonal hematopoiesis has been shown to increase the risk of developing tMN. The value of analyzing hematopoietic stem cells harvested at leukapheresis before autologous stem cell transplantation (ASCT) with next-generation sequencing and immunophenotyping represents potentially informative parameters that have yet to be discovered. We performed a nested case-control study to elucidate the association between clonal hematopoiesis, mobilization potential, and aberrant immunophenotype in leukapheresis products with the development of tMN after ASCT. A total of 36 patients with nonmyeloid disease who were diagnosed with tMN after treatment with ASCT were included as case subjects. Case subjects were identified from a cohort of 1130 patients treated with ASCT and matched with 36 control subjects who did not develop tMN after ASCT. Case subjects were significantly poorer mobilizers of CD34+ cells at leukapheresis (P = .016), indicating that these patients possess inferior bone marrow function. Both clonal hematopoiesis (odds ratio, 5.9; 95% confidence interval, 1.8-19.1; P = .003) and aberrant expression of CD7 (odds ratio, 6.6; 95% confidence interval, 1.6-26.2; P = .004) at the time of ASCT were associated with an increased risk of developing tMN after ASCT. In conclusion, clonal hematopoiesis, present at low variant allele frequencies, and aberrant CD7 expression on stem cells in leukapheresis products from patients with nonmyeloid hematologic cancer hold potential for the early identification of patients at high risk of developing tMN after ASCT.

show abstract

Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation

Abstract: Highlights d Autologous stem cell transplantation promotes the expansion of mutant blood clones d CHIP-mutated human stem cells engraft long term and dominate blood reconstitution d Neutrophil reconstitution post-transplantation is delayed in patients with CHIP

Cited by 52 publications

References 36 publications

Association between Clonal Hematopoiesis and Late Nonrelapse Mortality after Autologous Hematopoietic Cell Transplantation

Association between Clonal Hematopoiesis and Late Nonrelapse Mortality after Autologous Hematopoietic Cell Transplantation

Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia

Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post–autologous stem cell transplantation

Contact Info

Product

Resources

About