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  • 1
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    Online Resource
    Mutational Shift in FLT3 and NPM1-Positive Acute Myeloid Leukemia (AML) Relative to Therapy and Disease Progression
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2866-2866
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2866-2866
    Abstract: Introduction: Clonal myeloid malignancies such as AML are often characterized and treated based on specific mutation profiles identified at diagnosis. Routine use of clinical cancer next-generation sequencing (NGS) in diagnosis and disease monitoring has resulted in sequential mutation profiles of individual patients. On NGS profiling at interval follow-ups, mutations identified at diagnosis may change, or shift, through disease course. Here we track FLT3 and NPM1 mutations in the context of therapy, disease progression, clinical course, and pathology. Methods: Patients with AML or MDS whose blood or marrow specimens were sequenced using the Penn hematological-NGS panel (68 genes with full exon coverage) on at least 2 occasions and found at least once to have FLT3 or NPM1 mutations were included. An R script was written to track mutations and allele frequencies over time. These data were integrated with corresponding pathology and clinical data to evaluate mutation profiles in relation to disease status, therapy and progression. This study was approved by the institutional review board. Results: Review of clinical NGS data identified 37 patients with pathogenic mutations in FLT3 (n=15), NPM1 (n=5), or FLT3 and NPM1 (n=17) in samples characterized as de novo AML (AML), recurrent AML (rAML), myelodysplastic syndrome (MDS), recurrent MDS (rMDS), AML transformed from MDS (tAML), or AML in remission (R). Patients were divided into 3 mutational groups: FLT3 only, FLT3 and NPM1, and NPM1 only. The average number of pathogenic mutations (including mutations in genes other than FLT3 or NPM1) at initial and second testing was 1.9/3.1; 3.5/3.4 and 3.2/1.8, respectively. Tracking of FLT3 and NPM1 allele frequencies ( 〉 10% change) revealed changes in populations of multiple subclones at different time points. In the FLT3 and FLT3 and NPM1 groups, the original FLT3 and/or NPM1 mutation often became undetectable at subsequent testing. This frequently coincided with the emergence of new clones with different mutations. Nineteen patients showed loss of an original FLT3 mutation at subsequent testing, with 11 of these patients showing emergence of a new FLT3 clone with a different mutation. All 11 patients with loss of an original NPM1 clone had a new NPM1 clone with a different mutation appear. The NPM1 only group did not show loss of the original NPM1 clone unless it was at remission. All five patients in the NPM1 only group (3 AML, 2 rAML at initial CPD testing) achieved clinical and histologic remission with concordant loss of NPM1 mutations. In four patients, the detectable mutations remaining at remission were exclusively from the original clone (DNMT3A, DNMT3A/TET2, DNMT3A/IDH2/TET2, IDH2). The fifth patient had a newly detected SRSF2 mutation in addition to the original IDH2 mutation. All five patients are alive, and do not have overt morphologic evidence of recurrent AML on bone marrow biopsies that were performed within the last year. In four AML patients with FLT3 mutations, of which three were on FLT3 inhibitor therapy, the loss of a FLT3 mutation was followed by the emergence of a new NRAS mutation. Three patients achieved remission, but two died soon after of complications from graft versus host disease. The fourth patient achieved remission and had a detectable mutation only in IDH2, but on subsequent NGS testing showed reemergence of the previous NRAS mutation and relapsed three months later. Conclusions: Monitoring of FLT3 and NPM1 mutations in AML patients by NGS rather than single gene assays is crucial due to the frequent findings of other pathogenic co-mutations, mutational shift in response to disease progression and to therapy, and emergence of new disease associated clones at recurrence. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2866.2866
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 2
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    Abstract 5609: Next generation sequencing in acute myeloid leukemia: Correlation with cytogenetic studies highlighting different spectrums of mutations
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5609-5609
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5609-5609
    Abstract: Acute myeloid leukemia (AML) represents a heterogeneous group of aggressive myeloid malignancies characterized by the accumulation of blasts in the bone marrow. The prognosis of AML is variable, likely reflecting its diversity at a genetic level. The pathogenesis of AML has not been completely defined; however it is clear that recurrent chromosomal abnormalities (e.g., translocations and numeric abnormalities) and genetic events (e.g., point mutations and indels) are necessary for disease development. Genetic changes are diverse and consist of large genomic changes such as rearrangements and ploidy anomalies, as well as submicroscopic changes, including point mutations and indels. Few studies have correlated cytogenetically detected anomalies with molecularly detected mutations in AML. Here we describe our experience using a hematological next generation sequencing (heme-NGS) panel in conjunction with conventional cytogenetic studies to interrogate diagnostic AML specimens in a routine clinical setting. Next generation sequencing was done using a custom designed amplicon panel and Illumina TruSeq Custom Amplicon (TSCA) capture. Using a customized bioinformatics pipelines we were able to detect single nucleotide variants (SNV) and small insertion/deletion (indel) to a lower limit of 5% with 100% sensitivity and specificity. 28 genes recurrently mutated in myeloid malignancies were examined including targeted regions of NPM1, FLT3, KIT, PTPN11, NRAS, IDH1, IDH2, JAK2, DNMT3a, EZH2, PTEN, CEBPA, TP53, WT1, RUNX1, TET2, ATM, BRAF, CBL, MPL, SF3B1, ASXL1, HRAS, KRAS, PHF6, GNAS, ETV6 and MYD88. Over 100 specimens were analyzed by NGS and cytogenetics , with only a single case being ‘normal’ by both tests. Comparison of mutation-positive AML demonstrated more mutations present in cytogenetically normal cases, compared with those with chromosome abnormalities detected. Conversely, in 11 cases no mutations were detected by heme-NGS, with 10/11 of these cases showing recurrent cytogenetic abnormalities. In those cases where NGS mutations were identified, comparison of cases with normal (CN-AML) and abnormal (CA-AML) cytogenetic studies demonstrated different mutation frequencies, with more mutations detected in CN-AML. Interestingly, TP53 was the most commonly mutated gene in CA-AML and least mutated in CN-AML. These results illustrate the complementary information gained from NGS sequencing performed with conventional cytogenetic studies in diagnostic AML specimens, providing a comprehensive picture of the genomic landscape in this disease. A complete description of these combined cytogenetic and molecular abnormalities seen in AML and correlation with clinical features will be presented. Citation Format: Robert B. Daber, Jianhua Zhao, Martin Carroll, Craig Solderquest, Selina Luger, Gerald B.W. Wertheim, Adam Bagg, Jennifer J.D. Morrissette. Next generation sequencing in acute myeloid leukemia: Correlation with cytogenetic studies highlighting different spectrums of mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5609. doi:10.1158/1538-7445.AM2014-5609
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-5609
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
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    Online Resource
    Limited FISH Testing for MDS-Defining Cytogenetic Abnormalities Rapidly Identifies Patients with Newly Diagnosed AML Eligible for CPX-351
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4785-4785
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4785-4785
    Abstract: Introduction: CPX-351 (liposomal cytarabine and daunorubicin; VYXEOS) improves survival and complete remission rates compared to standard induction chemotherapy (7+3) in patients 60 to 75 years old with newly diagnosed myelodysplastic syndrome (MDS)-associated and therapy-related AML (Lancet et al., JCO 2018) and was approved by the U.S. Food and Drug Administration in August 2017. In addition to patients with a known history of MDS or cytotoxic and/or radiotherapy, patients with de novo AML with WHO-defined MDS-related cytogenetic changes are also eligible for CPX-351. We have implemented a diagnostic clinical pathway for patients with newly diagnosed AML which includes rapid FISH assessment for the most common MDS-defining karyotypes in patients who are potential candidates for CPX-351. We reviewed outcomes after the first year of this diagnostic pathway in our institutional cohort comparing results of chromosome metaphase analysis and rapid FISH. Methods: We performed both rapid MDS-FISH testing (turnaround time 〈 6 hours) and metaphase analysis on all patients who presented to the University of Pennsylvania from 9/2017 through 6/2018 with newly diagnosed AML who were potential candidates for CPX-351 induction therapy based on age and other clinical factors. Our MDS-FISH panel includes probes for EGR1(5q31)/5p15.2, D7S486(7q31)/CEP7, and TP53(17p13.1)/NF1(17q11.2) (MetaSystems). Results of the limited FISH testing were compared with metaphase chromosome analysis. Demographic and clinical information was abstracted from the electronic medical record. This study was approved by the University of Pennsylvania Institutional Review Board. Results: Twenty-nine patients with newly diagnosed AML from 9/2017 through 6/2018 had both rapid MDS-FISH and karyotype testing performed. Nineteen patients (65.5%) had de novo AML, while 7 (24.1%) had a clinical history of MDS and 3 (10.3%) had a history of prior cytotoxic and/or radiation therapy. Metaphase analysis revealed WHO-defined MDS-related cytogenetic abnormalities in 14/29 patients (48.3%). Of these 14 patients, 11 (78.6%) also had positive MDS-FISH testing in 〉 =1 probe. Of the 3 patients with MDS-related cytogenetic abnormalities that were identified by metaphase analysis but not the FISH panel, 2 had a history of either MDS (n=1) or prior cytotoxic chemotherapy (n=1) and therefore were eligible for CPX-351 based on clinical history alone. Of the 7 patients with de novo AML and MDS-defining cytogenetic abnormalities, 6 (85.7%) were identified by the FISH screen. Conclusions: Rapid FISH testing for MDS-defining cytogenetic changes using probes for abnormalities of chromosomes 5, 7, and 17 efficiently identifies the majority of patients with newly diagnosed de novo AML who do not have a clinical history of MDS or cytotoxic therapy but are eligible for induction therapy with CPX-351 based on the presence of MDS-defining cytogenetic abnormalities. The combination of rapid FISH testing and clinical history has a high sensitivity for identifying patients with MDS-defining karyotypic abnormalities. This diagnostic clinical pathway allows for the expeditious identification of patients eligible for CPX-351. Disclosures Frey: Servier Consultancy: Consultancy; Novartis: Consultancy. Perl:Astellas: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116415
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 4
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    Outcomes of Allogeneic Stem Cell Transplantation for AML and MDS Based on Pre-Transplant MRD Status By Next-Generation Sequencing
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2134-2134
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2134-2134
    Abstract: Background After induction therapy for acute myelogenous leukemia (AML), the presence of minimal residual disease (MRD) by targeted next-generation sequencing (NGS) during complete remission (CR) predicts relapse and survival, particularly after exclusion of pre-leukemic mutations. MRD assessment is not routinely performed for AML prior to transplant, partly because consensus regarding assay methodology, appropriate timing, interpretation of results, and therapeutic value prior to SCT is lacking. We therefore sought to describe the rates of mutational clearance and correlate these with relapse rates post-transplant. Methods We conducted a retrospective review of sequential AML or myelodysplastic syndrome (MDS) patients undergoing allogeneic hematopoietic cell transplant (alloHCT) at our institution between 2014 and 2017. There were 119 patients with AML/MDS who were treated with either myeloablative or reduced intensity conditioning regimens. Of the 119 patients transplanted, 60 had both pre- and post-treatment NGS results and were included in the analysis. 56 patients had somatic mutations on initial NGS and were therefore eligible for mutational clearance analysis. Twelve patients were in active disease and excluded from further analyses. The remaining patients (n=44) represent the core dataset. Blood and/or marrow specimens were analyzed via a clinical NGS panel targeting 68 leukemia-associated genes. Median coverage (across 88 samples) was 2817 reads. Mutations were considered persistent if present at variant allele frequencies (VAF) ≥ 1% for single nucleotide variants (SNV) or ≥ 2 copies for insertions and deletions (indels). Validated laboratory reporting practice at our institution reports VAF 〉 4% for SNVs and ≥ 1% for indels with a minimum of 250 total reads. We therefore defined three levels of mutational clearance on the basis of the VAF of residual mutations: VAF for SNV 〈 1% (and/or indels ≤1 copy), between 1-4% (and/or indels 〈 1% and ≥ 2 copies), and 〉 4% (and/or indels 〉 1%). Patients with ≥ 1 mutation meeting these thresholds were designated NGS(-), NGS-low and NGS(+), respectively. The median follow-up was 332 days. Results On review of NGS data, 120 mutations were present in initial sequencing, with 64 mutations persistent in pre-transplant samples from 26 patients. The most commonly mutated genes from initial samples were FLT3 (18), ASXL1 (11), TET2 (10), NPM1 (9), RUNX1 (8), SRSF2 (8), and DNMT3A (7) (Figure 1A). Mutational clearance varied widely, with the putative pre-leukemic genes DNMT3A, TET2, and ASXL1 (DTA) demonstrating low rates of mutational clearance (Figure 1A). Mutations persisting below the validated reporting threshold were present in 20 patients, including 10 patients otherwise negative by NGS. There were 16 patients categorized as NGS(+), 10 NGS-low, and 18 NGS(-), with relapse rates of 31%, 22%, and 30%, respectively. No difference in relapse risk was observed between NGS(-) and NGS-low subgroups (p = 0.72), and no RFS benefit was observed for patients without persistent mutations 〉 4% relative to the NGS(+) subgroup (p = 0.56, Figure 1B). Recent work has shown a survival benefit in AML patients in CR without persistent mutations that is enhanced when DTA genes were excluded from the analysis (Jongen-Lavrencic, NEJM 2018). In our cohort, after exclusion of DTA mutations, 6 patients were reclassified by mutational clearance status, and 2 were excluded from the analysis as they had only DTA mutations in pre-treatment samples. Similar to the more comprehensive cohort, no RFS benefit based on NGS status was observed in the post-transplant period (p = 0.42, Figure 1C). Conclusions There were similar outcomes regardless of molecular MRD findings by NGS for patients with advanced myeloid malignancies who were in morphologic CR prior to alloHCT. These results contrast with those in the published literature that address a more uniform patient population of clinical trial participants, not all of whom went on to transplant. Further detailed analyses from larger more homogeneous populations will be useful to determine the prognostic significance of MRD by NGS prior to allogeneic HCT. Figure 1 Figure 1. Disclosures Frey: Servier Consultancy: Consultancy; Novartis: Consultancy. Perl:Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Daiichi Sankyo: Consultancy. Stadtmauer:Takeda: Consultancy; Celgene: Consultancy; AbbVie, Inc: Research Funding; Amgen: Consultancy; Janssen: Consultancy. Porter:Genentech: Other: Spouse employment; Kite Pharma: Other: Advisory board; Novartis: Other: Advisory board, Patents & Royalties, Research Funding. Gill:Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership; Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-117410
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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