NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse by Alexander Höllein, Manja Meggendorfer, Frank Dicker,

Slides:

Advertisements

Similar presentations

Supervisor: VS 高志平 Reporter: R4 張妙而.  Mutations in nucleophosmin 1 ( NPM1 ) gene, one of the most common gene mutations (25%-30%) in AML  NPM1 mut co-occurs.

Advertisements

Recurrent SETBP1 mutations in atypical chronic myeloid leukemia Nature Genetics.

Hairy Cell Leukemia Variant Has Similar Survival to Classical Disease Despite Poorer Responses to Initial Therapy: A 30-Year Experience from Memorial Sloan.

May 29 - June 2, 2015 Leukemia Stem Cell Phenotypes Correlate With Cytogenetic Risk Factors and Outcomes CCO Independent Conference Highlights of the 2015.

Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia by Klaus H. Metzeler, Tobias Herold, Maja Rothenberg-Thurley, Susanne.

Identification of mutations prognostic of relapse after allogeneic transplantation and novel clone emergence at disease recurrence: implications for strategies.

Margaret L. Gulley, Thomas C. Shea, Yuri Fedoriw

1 Stone RM et al. Proc ASH 2015;Abstract 6.

PROGNOSTIC SIGNIFICANCE OF GENE MUTATIONS IN MDS DEPENDS ON THE LOCI OF GENE VARIANCES PROGNOSTIC SIGNIFICANCE OF GENE MUTATIONS IN MDS DEPENDS ON THE.

Clearance of ‘Driver-COSMIC’ mutations post-CR1 with persisting RUNX1_L56S is unlikely to contribute towards disease progression L . Rai1, T. Boneva1,

Clinical Implications of Non-A-Type NPM1 and FLT3 Mutations in Patients with Normal Karyotype Acute Myeloid Leukemia Acta Haematol 2012;127:63–71.

Image 1 Detection of minimal residual disease (MRD) in consecutive bone marrow (BM) samples from a patient with relapse (A) and a patient still in remission.

by David Grimwade, Adam Ivey, and Brian J. P. Huntly

High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated.

Margaret L. Gulley, Thomas C. Shea, Yuri Fedoriw

A next-generation sequencing–based assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations by Mark J. Levis, Alexander E.

Rapid Identification Of Compound Mutations In Patients With Ph-Positive Leukemias By Long-Range Next Generation Sequencing by Sandra Preuner, Renate Kastner,

Multicolor Flow Cytometry and Multigene Next-Generation Sequencing Are Complementary and Highly Predictive for Relapse in Acute Myeloid Leukemia after.

Figure S1. AML550 and AML719 arrays

Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value by Saman.

Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia

Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling by.

Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with.

Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia by Tatsuya Imi, Takamasa Katagiri, Kazuyoshi.

Clinical Implications of Clonal Hematopoiesis

A novel hierarchical prognostic model of AML solely based on molecular mutations by Vera Grossmann, Susanne Schnittger, Alexander Kohlmann, Christiane.

The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML by Nona Shayegi, Michael Kramer,

Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis- Associated Mutations throughout Adult Life Rocio Acuna-Hidalgo, Hilal Sengul,

Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma by Hannes Kaufmann, Markus Raderer, Stefan Wöhrer,

by R. Coleman Lindsley, and Benjamin L. Ebert

Global approach to the diagnosis of leukemia using gene expression profiling by Torsten Haferlach, Alexander Kohlmann, Susanne Schnittger, Martin Dugas,

ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase.

Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common.

Mutated regions of nucleophosmin 1 elicit both CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia by Jochen Greiner, Yoko Ono, Susanne.

Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia by Floriana Manodoro, Jacek Marzec, Tracy.

by Zachary R. Hunter, Lian Xu, Nickolas Tsakmaklis, Maria G

Allogeneic Stem Cell Transplantation Improves Survival in Patients with Acute Myeloid Leukemia Characterized by a High Allelic Ratio of Mutant FLT3-ITD

Cell-lineage level–targeted sequencing to identify acute myeloid leukemia with myelodysplasia-related changes by Kazuaki Yokoyama, Eigo Shimizu, Nozomi.

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy by Sara Mastaglio, Eric Wong, Travis.

Patterns of Somatically Acquired Amplifications and Deletions in Apparently Normal Tissues of Ovarian Cancer Patients Leila Aghili, Jasmine Foo, James.

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy by Jean-François Spinella, Chantal Richer,

Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia by Philip.

Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA by Nikola P. Konstandin, Friederike Pastore, Tobias Herold, Annika Dufour,

Overall survival by SCT versus observation in first complete remission

Impact of somatic and germline mutations on the outcome of systemic mastocytosis by Javier I. Muñoz-González, María Jara-Acevedo, Iván Alvarez-Twose, Jason.

Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines by Yanyan Zhang, Liang He, Dorothée.

Emerging Importance of Mutational Analysis in Myelodysplastic Syndrome and Acute Myelogenous Leukemia Aaron T. Gerds, Matthew J. Walter, Bart L. Scott

Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity by Mary Eapen, Ruta Brazauskas, Michael.

PHF6 and DNMT3A mutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation by Wenbin Xiao, Maheetha.

by Hassan Awada, Yasunobu Nagata, Abhinav Goyal, Mohammad F

Strategy for Robust Detection of Insertions, Deletions, and Point Mutations in CEBPA, a GC-Rich Content Gene, Using 454 Next-Generation Deep-Sequencing.

Immunoglobulin and T Cell Receptor Gene High-Throughput Sequencing Quantifies Minimal Residual Disease in Acute Lymphoblastic Leukemia and Predicts Post-

Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications by Daria V. Babushok, Jamie L. Duke,

by Ayalew Tefferi, Terra L. Lasho, Paola Guglielmelli, Christy M

Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy by Zimu Gong, L. Jeffrey Medeiros, Jorge.

Patterns of Somatically Acquired Amplifications and Deletions in Apparently Normal Tissues of Ovarian Cancer Patients Leila Aghili, Jasmine Foo, James.

by Terra L. Lasho, Mythri Mudireddy, Christy M. Finke, Curtis A

Clinical, molecular, and immunological responses to pembrolizumab treatment of synchronous melanoma and acute myeloid leukemia by Anne Sophie Kubasch,

by Giovanni Palladini, and Giampaolo Merlini

NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy by Guillermo Montalban-Bravo,

Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia by Sebastian.

Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study by Guillermo Garcia-Manero, Yasmin.

Progression-free (a) and overall (b) survival by age subgroup, Kaplan-Meier plots. Progression-free (a) and overall (b) survival by age subgroup, Kaplan-Meier.

CIP2A- and SETBP1-mediated PP2A inhibition reveals AKT S473 phosphorylation to be a new biomarker in AML by Claire M. Lucas, Laura J. Scott, Natasha Carmell,

by Jan J. Cornelissen, and Didier Blaise

Molecular definitions of lung adenocarcinoma subtypes.

Interleukin-6 levels predict event-free survival in pediatric AML and suggest a mechanism of chemotherapy resistance by Alexandra M. Stevens, Jennifer.

by Monika Brüggemann, and Michaela Kotrova

Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and.

How I treat T-cell acute lymphoblastic leukemia in adults

Presentation transcript:

NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse by Alexander Höllein, Manja Meggendorfer, Frank Dicker, Sabine Jeromin, Niroshan Nadarajah, Wolfgang Kern, Claudia Haferlach, and Torsten Haferlach BloodAdv Volume 2(22):3118-3125 November 27, 2018 © 2018 by The American Society of Hematology

Alexander Höllein et al. Blood Adv 2018;2:3118-3125 © 2018 by The American Society of Hematology

AML relapse with NPM1mut occurs earlier than relapse with NPM1wt. AML relapse with NPM1mutoccurs earlier than relapse with NPM1wt. (A) RFS of patients with NPM1mut relapse and NPM1wt relapse. (B) OS following relapse of patients with NPM1mut relapse and NPM1wt relapse. 95% CI, 95% confidence interval; OS, overall survival; RFS, relapse-free survival. Alexander Höllein et al. Blood Adv 2018;2:3118-3125 © 2018 by The American Society of Hematology

DNMT3A mutations at diagnosis are associated with NPM1wt relapse. DNMT3A mutations at diagnosis are associated with NPM1wtrelapse. Cooccurring mutations with NPM1 at diagnosis of all patients. For 61/90 patients with NPM1mut relapse and for 11/14 patients with NPM1wt relapse, the diagnostic sample was available for 63 gene panel sequencing. Shown are mutations in genes affected in >10% of cases. DNMT3A mutations are significantly more frequent in patients that relapse with NPM1wt disease. FLT3-ITD mutations are significantly more frequent in patients that relapse with NPM1mut disease. n.a., not available. Alexander Höllein et al. Blood Adv 2018;2:3118-3125 © 2018 by The American Society of Hematology

NPM1wt relapse is associated with persistent mutations. NPM1wtrelapse is associated with persistent mutations. (A) For 11/14 patients with NPM1wt relapse, paired samples at diagnosis and relapse were available for sequencing. Shown are genes mutated at least once in the analyzed samples. Genes with >1 mutation/patient are shown once. (B) Number of persistent mutations at relapse; median, 2 (range, 0-4). (C) Left: mutations in 7 genes detected at diagnosis were found to persist at relapse. Fraction of persistent mutations in relation to all 11 patients is shown. Right: The 4 most frequently mutated genes at D and R are shown as heat maps to visualize persistence of mutations. DNMT3A is the most prevalent mutation and also the most stable mutation over time. (D) The variant allele frequency of the indicated genes is given at D and R. D, diagnosis; R, relapse. Alexander Höllein et al. Blood Adv 2018;2:3118-3125 © 2018 by The American Society of Hematology

Premalignant clonal hematopoiesis underlies NPM1wt relapse. Premalignant clonal hematopoiesis underlies NPM1wtrelapse. (A) For 9/11 patients, 2 remission samples/patient were available for sequencing analysis. Eights of 9 patients showed persistent mutations in CMR and 4 patients acquired additional mutations before the onset of relapse. (B) Mutations in 6 genes detected at diagnosis were found to persist in remission. Shown is the fraction of persistent mutations in relation to all 9 patients. (C) VAF of persisting mutations at diagnosis, CMR, and relapse. Black line, median; CR, complete remission. Alexander Höllein et al. Blood Adv 2018;2:3118-3125 © 2018 by The American Society of Hematology

NPM1mut allelic burden and DNMT3A mutation type is not associated with NPM1wt relapse. NPM1mutallelic burden and DNMT3A mutation type is not associated with NPM1wtrelapse. (A) The variant allele fraction of NPM1, DNMT3A, TET2, and FLT3-TKD mutations at diagnosis of the indicated cohort. (B) The fraction of DNMT3A R882 mutations at diagnosis for the indicated cohort (n = 22 NPM1mut relapse, n = 9 NPM1wt relapse, NS). (C) At CMR, 11/15 patients in the cohort with NPM1mut relapse showed a persistent DNMT3A mutation and 6/9 in the cohort with NPM1wt relapse. Shown is the fraction of persistent DNMT3A R882 mutations in the respective cohort (NS). Alexander Höllein et al. Blood Adv 2018;2:3118-3125 © 2018 by The American Society of Hematology

Model for clonal hematopoiesis driving relapse or secondary leukemia. Model for clonal hematopoiesis driving relapse or secondary leukemia. The first leukemia is cured by chemotherapy based on the underlying clonal hematopoiesis; a second driver mutation than leads to overt relapse. Alexander Höllein et al. Blood Adv 2018;2:3118-3125 © 2018 by The American Society of Hematology