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  • 1
    Online Resource
    Online Resource
    Patient-Tailored Measurable Residual Disease Monitoring in Peripheral Blood Using Deep Sequencing and Droplet Digital PCR for Early Detection of Relapse in Childhood Acute Myeloid Leukemia: A NOPHO-DBH Collaborative Study
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3457-3457
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3457-3457
    Abstract: Close surveillance of measurable residual disease (MRD) following completion of therapy for acute myeloid leukemia (AML) enables early detection of relapse in time for pre-emptive treatment. Today this is available only for the fraction of patients with recurrent targets quantifiable with standardized RT-qPCR. Patient-tailored MRD monitoring based on leukemia-specific mutations may be an attractive option in patients lacking such aberrations. In this population-based study, we used whole exome sequencing (WES) to identify leukemia-specific mutations suitable for MRD monitoring, and targeted deep sequencing (deep seq) and droplet digital PCR (ddPCR) for quantitative monitoring in children with AML. We investigated the clinical applicability of patient-tailored deep seq and ddPCR for early detection of AML relapse in peripheral blood (PB). All children (0-18 years) with de novo AML diagnosed between March 2013 and December 2018 who achieved complete remission after treatment according to the NOPHO-DBH AML 2012 protocol (EudraCT number: 2012-002934-35) in Sweden, Denmark, the Netherlands, Norway and Finland were eligible for the study (n = 179). In the study, patients had PB samples drawn at monthly intervals and biobanked for retrospective analyses of leukemia-specific mutations. In patients with a marker for RT-qPCR, samples were also analyzed with RT-qPCR with results reported back to the clinic. Included patients (n = 134) had PB samples drawn starting one month after last consolidation course or date of allogeneic stem cell transplantation and until relapse or end of follow-up (12-18 months following therapy completion), (median 11 samples/patient, range 1-28). Out of the 34 patients who experienced relapse during the study period, sufficient biological material for WES at diagnosis was available from 26 patients (21 hematologic and 5 molecular relapses as determined by RT-qPCR in patients with a suitable marker). For these 26 patients, the median time from end of therapy to relapse (hematologic or molecular) was 6.7 months (range 3.1-23.7). In 24/26 patients, leukemia-specific mutations could be identified at diagnosis. For 22/24 patients, leukemia-specific mutations were verified to be present at relapse (hematologic or molecular) either by WES or deep seq. In the remaining two patients with molecular relapse, leukemia-specific mutations were not verified at molecular relapse. In the 22 patients where leukemia-specific mutations could be detected, 55 mutations (median 3/patient, range 1-4) were quantified with deep seq (limit of detection [LoD] 0.02% variant allele frequency [VAF] ) in 111 PB samples (263 analyses) with a sampling interval of 0.9 months (range 0.2-2.6). Parallel ddPCR analyses of 43 mutations from 20 of these patients were performed in 100 PB samples (206 analyses) with a median LoD of 0.04% VAF (range 0.003-0.1%). Deep seq and ddPCR were concordant in 187/206 (91%) of analyses and 84/100 (84%) of analyzed samples. Median VAF in the 113 paired analyses with MRD level above LoD was 0.34% (range 0.02-47.23) with deep seq and 0.38% (range 0.02-45.97) with ddPCR (P = 0.7). Obtained VAFs correlated strongly between the two methods (Spearman's ρ 0.91, P & lt; 0.0001). Nineteen of the analyzed patients experienced hematologic relapse and in 17 of these, at least one mutation was detected in blood before relapse. The median lead time from MRD positivity to hematologic relapse was 3.2 months (range 0.6-7.9) when analyzed with deep seq (n = 17) and 2.6 months (range 0.5-7.9) when analyzed with ddPCR (n = 15). Lead times in patients analyzed with both deep seq and ddPCR showed comparable Kaplan-Meier curves (Fig. 1A). Additional comparison of the lead times achieved with deep seq/ddPCR and RT-qPCR of WT1 expression (n = 6) and recurrent genetic aberrations (n = 5) showed similar Kaplan-Meier curves (Fig. 1B-C). As assessed by deep seq in patients who were not pre-emptively treated, relapse kinetics varied greatly between patients; median VAF doubling time was 12 days with a range of 4-43 (n = 17). In conclusion, highly sensitive quantification of leukemia-specific mutations in a patient-tailored manner using deep seq or ddPCR enables post-treatment monitoring for the majority of children with AML. Frequent assessment in blood may allow for timely identification of pending relapses to initiate pre-emptive treatment strategies. Figure 1 Figure 1. Disclosures Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-153411
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Patient-Tailored Deep Sequencing of Peripheral Blood Enables Early Detection of Relapse in Childhood Acute Myeloid Leukemia
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1456-1456
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1456-1456
    Abstract: Relapse remains a major therapeutic challenge in children with acute myeloid leukemia (AML). Outcome after relapse may improve if preemptive therapy is initiated at first evidence of leukemia regrowth. Early detection of imminent relapse requires molecular measurable residual disease (MRD) monitoring after therapy completion. Today, this is possible only in about 40% of children with AML that harbor genetic abnormalities applicable for quantification using standardized qPCR assays. To enable disease surveillance for all patients, we developed patient-tailored deep sequencing (DS) MRD analysis, which provides highly sensitive detection of leukemia-specific mutations. We investigated the potential of this method for early relapse detection in peripheral blood (PB), the only easily accessible source for MRD sampling in children. PB samples were collected at monthly intervals during follow-up from 45 children diagnosed with AML and treated according to The Nordic Society of Pediatric Haematology and Oncology (NOPHO)-DBH AML 2012 protocol between January 2013 and May 2016 in Denmark, Norway, Sweden and Finland (508 samples, median 11 samples/patient, range 3-27). Nine patients with relapse (median age 5 years, range 0-8) had available diagnostic and relapse material and were included in this study. The patients displayed core binding factor abnormalities (n=3), KMT2A-rearrangements (n=3), monosomy 7 (n=1) or normal karyotype (n=2) at AML diagnosis. Leukemia-specific single nucleotide variants (SNVs) were identified with exome sequencing (ES) of sorted leukemic cells with lymphocytes or remission PB as constitutive DNA template. A variant allele frequency (VAF) with 95% confidence interval including 50% indicates presence of the mutation in all leukemic cells at diagnosis. With the exception of 2 cases with only subclonal mutations at diagnosis, leukemia-specific SNVs with VAF of 50% at diagnosis and persistence at relapse were selected as MRD targets. MRD target mutations were quantified in PB samples preceding overt relapse using patient-tailored DS assays with sensitivity of VAF 0.02%. In diagnostic samples, ES identified 53 leukemia-specific SNVs (median 4 SNVs/patient, range 2-12) of which 33 were also present at relapse (median 2 SNVs/patient, range 1-9). The number of mutations identified at diagnosis increased with age (Rs 0.83, p=0.006). All patients had at least one leukemia-specific SNV detected at both diagnosis and relapse. Twenty-one MRD target mutations (median 2 SNVs/patient, range 1-3) were quantified in PB (55 samples, median sampling interval 28 days, range 11-80) using DS. In 8/9 patients, at least one SNV was detected in PB before overt relapse occurred. The first PB sample showing MRD positivity (median VAF 0.14%, range 0.03-0.44) preceded hematological relapse at a median interval of 3 months (range 0-7.9). In 6 patients not preemptively treated, the median doubling time based on VAF increments was 7 days, with great variability between individuals and genotypes (range 4-28 days). Three patients had molecular relapse diagnosed by qPCR used in clinical diagnostics and received individualized preemptive treatment. In these 3 patients, DS detected mutations in PB for & gt;100 days preceding overt relapse and the doubling times were 14, 25 and 36 days. In conclusion, DS of leukemia-specific mutations at frequent intervals in PB enables early detection of relapse and ES at diagnosis may identify SNVs applicable for such longitudinal MRD monitoring. This approach facilitates molecular disease surveillance and initiation of preemptive therapy in AML patients without established qPCR targets. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-124970
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 3
    Online Resource
    Online Resource
    Accurate and Sensitive Analysis of Minimal Residual Disease in Acute Myeloid Leukemia Using Deep Sequencing of Single Nucleotide Variations
    Elsevier BV ; 2019
    In:  The Journal of Molecular Diagnostics Vol. 21, No. 1 ( 2019-01), p. 149-162
    Details
    In: The Journal of Molecular Diagnostics, Elsevier BV, Vol. 21, No. 1 ( 2019-01), p. 149-162
    Type of Medium: Online Resource
    ISSN: 1525-1578
    URL: Article
    DOI: 10.1016/j.jmoldx.2018.08.004
    RVK:
    XA 55072
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
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  • 4
    Online Resource
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    MicroRNA-708 is a novel regulator of the Hoxa9 program in myeloid cells
    Springer Science and Business Media LLC ; 2020
    In:  Leukemia Vol. 34, No. 5 ( 2020-05), p. 1253-1265
    Details
    In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 5 ( 2020-05), p. 1253-1265
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
    URL: Article
    DOI: 10.1038/s41375-019-0651-1
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2008023-2
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  • 5
    Online Resource
    Online Resource
    Members of the microRNA-106a-363 Cluster Associate with Unfavorable Outcome in Adult Acute Myeloid Leukemia Patients and Promote Leukemogenesis invivo through Increased Metabolic Activity
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3924-3924
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3924-3924
    Abstract: The miR-106a-363 cluster, encoding six miRNAs (miR-106a, miR-18b, miR-20b, miR-19b, miR-92a and miR-363), is a paralogue of the oncogenic miR-17-92a polycistron and its role in leukemia is at present largely unknown. We aimed to investigate the putative oncogenic role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML) and to dissect the contributions of its individual members to disease formation and progression. First, we analyzed the expression of each miRNA in AML patient samples as well as their clinical relevance. To determine the association of the miR-106a-363 cluster in AML with active disease, we quantified all six miRNAs individually in AML patient samples at initial diagnosis (n=33) and in AML patients in complete remission after chemotherapy (n=6). Hereof, miR-106a-5p, miR-19b-3p and miR-92a-3p levels were significantly lower in remission samples (p=0.0015, p=0.0013 and p=0.0004, respectively), confirming that these miRNAs are upregulated in AML. Stratifying AML patients within the LAML miRNA-Seq dataset of The Cancer Genome Atlas (TCGA) Research Network (n=187) (Ley et al., NEJM, 2013) according to their cytogenetic risk group demonstrated that all members of the cluster, except for miR-18b-5p, significantly associated with adverse cytogenetics. In addition, with the exception of miR-18b-5p, all members associated with an inferior overall survival (OS) in AML patients within the TCGA-LAML dataset, further supporting a pro-leukemogenic role for the cluster. Of note, miR-106a-5p was the most abundantly expressed unique miRNA of the polycistron, both in the TCGA patient cohort and in 11 myeloid leukemia cell lines quantified by quantitative real-time PCR (qRT-PCR). Since the miR-106a-363 cluster is associated with high risk AML, we hypothesized that increased levels of the entire cluster as well as individual members would significantly shorten the survival time in a murine transplantation model mimicking aggressive AML. Therefore, we engineered transplantable, primary murine AML cell lines based on retroviral overexpression of Hoxa9 and Meis1 exhibiting a median disease latency of 39 days (n=14) after syngeneic transplantation in mice. Enforced lentiviral expression of miR-106a-363 (n=13, p 〈 0.0001), miR-106a (n=15, p=0.0003), miR-18b (n=8, p 〈 0.0001), miR-20b (n=13, p 〈 0.0001) and miR-363 (n=13, p 〈 0.0001) in Hoxa9/Meis1 cells significantly accelerated leukemogenesis compared to the control arm. The most pronounced anemia (p=0.03) and the most immature phenotype, based on a significantly higher proportion of c-kit+ (p=0.0147) and a concurrent lower percentage of Mac-1+ and Gr-1+ (p=0.0051) cells, were observed in mice transplanted with Hoxa9/Meis1/miR-106a cells. Based on these results, we focused on the mechanism by which miR-106a contributed to the pathogenesis of AML and performed a proteomics screen comparing Hoxa9/Meis1/miR-106a and Hoxa9/Meis1/control cells. In particular, mitochondrial respiration processes, such as oxidative phosphorylation and electron transport chain components were induced by miR-106a as shown by Gene Set Enrichment Analysis. Preliminary results using high-resolution respirometry further indicated an increased number of mitochondria in Hoxa9/Meis1/miR-106a cells, supporting these findings. In conclusion, we highlight the previously unrecognized oncogenic contribution of the miR-106a-363 polycistron in adult AML. Functional dissection of this cluster, in particular miR-106a, revealed a new therapeutic angle for high risk AML. Disclosures Döhner: Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116035
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 6
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    Online Resource
    P468: DETECTION AND CHARACTERIZATION OF RESIDUAL LEUKEMIC CELLS IN CHILDHOOD ACUTE MYELOID LEUKEMIA USING TARGETED DEEP SEQUENCING AND SINGLE CELL MULTI-OMICS
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  HemaSphere Vol. 7, No. S3 ( 2023-08), p. e15552be-
    Details
    In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. S3 ( 2023-08), p. e15552be-
    Type of Medium: Online Resource
    ISSN: 2572-9241
    URL: Article
    DOI: 10.1097/01.HS9.0000968780.15552.be
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2922183-3
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  • 7
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    Online Resource
    Minimal residual disease assessed with deep sequencing of NPM1 mutations predicts relapse after allogeneic stem cell transplant in AML
    Informa UK Limited ; 2019
    In:  Leukemia & Lymphoma Vol. 60, No. 2 ( 2019-01-28), p. 409-417
    Details
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 60, No. 2 ( 2019-01-28), p. 409-417
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    URL: Article
    DOI: 10.1080/10428194.2018.1485910
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2019
    detail.hit.zdb_id: 2030637-4
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