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

ABSTRACT: 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.

SUBMITTER: Soerensen JF

PROVIDER: S-EPMC7065480 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Soerensen Johannes Frasez JF Aggerholm Anni A Kerndrup Gitte Birk GB Hansen Marcus Celik MC Ewald Ina Kathrine Lykke IKL Bill Marie M Ebbesen Lene Hyldahl LH Rosenberg Carina Agerbo CA Hokland Peter P Ludvigsen Maja M Stidsholt Roug Anne A

Blood advances 20200301 5

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 informa ...[more]

PMID: 32150606

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Project description:Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.

Project description:New strategies of autologous hematopoietic stem cell transplantation (auto-HSCT) have gained much interest for the treatment of type 1 diabetes mellitus. However, assessing the clinical response and residual ?-cell function still has limitations. The aim of the study was to select the optimal quantitative index to assess pre-existing ?-cell function and to explore its predictive function for clinical response after auto-HSCT therapy. In this study, all of the patients who had undergone auto-HSCT were clustered into a responder group (??-score > 0) and a nonresponder group (??-score ? 0). We compared their quantitative metabolic indexes at baseline and performed receiver-operating characteristic (ROC) analysis to analyze the correlations between the indexes and clinical response. Kaplan-Meier analysis was conducted to compare the cumulative response durations in each quartile of the selected indexes. In an average of 15.13 ± 6.15 months of follow-up, 44 of 112 patients achieved a clinical response. The responder group had lower levels of fasting plasma glucose and quantitative insulin sensitivity check index (QUICKI) but higher levels of fasting C-peptide, fasting insulin, and homeostasis model assessments for insulin resistance (HOMA-IR). ROC analysis showed that HOMA-IR had the largest area under the curve (0.756), which was similar to that of QUICKI. Kaplan-Meier analysis further confirmed that the third quartile (1.3371-1.7018) of HOMA-IR or the second quartile (0.3523-0.3657) of QUICKI was preferential for a prolonged response. In conclusion, HOMA-IR and QUICKI could be optimal measurements for ?-cell reserves, and they were predictive for the clinical response after auto-HSCT.The ?-score was comprehensive and reliable in evaluating clinical response after autologous hematopoietic stem cell transplantation (HSCT). The homeostasis model assessments for insulin resistance and the quantitative insulin sensitivity check index could serve as precise assessments for residual ?-cell function and good predictors of clinical response. They might be used to select optimal clinical trial participants or predict the clinical response after auto-HSCT.

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

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

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