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227 Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)Clinically Relevant Abstract

Acute Myeloid Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis
Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: Novel Molecular Markers for the Detection of Clonal Hematopoiesis and Minimal Residual Disease
Sunday, December 6, 2015: 10:30 AM
W110, Level 1 (Orange County Convention Center)

Silke Kapp-Schwoerer, MD1*, Andrea Corbacioglu, PhD1*, Verena I. Gaidzik, MD1*, Peter Paschka, MD1, Daniela Weber1*, Jan Kroenke, MD1*, Maria-Veronica Teleanu, MD1*, Gudrun Göhring, MD2*, Brigitte Schlegelberger, MD, PhD2, Michael Luebbert, MD3*, Thomas Kindler, MD4*, Mohammad Amen Wattad, MD5, Andrea Kuendgen, MD6*, David Nachbaur, MD7*, Walter Fielder, MD8*, Helmut Rainer Salih9, Heinz A. Horst, MD, PhD10, Karin Tina Mayer, MD11*, Katharina S. Götze, MD12, Martin Bentz, MD13, Jan Schleicher, MD14*, Felicitas Thol, MD15, Michael Heuser, MD15, Jürgen Krauter, MD16*, Arnold Ganser, M.D.15, Richard F. Schlenk, MD1, Hartmut Döhner, MD1* and Konstanze Döhner, MD1

1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
2Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
3Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany
4University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
5Department of Hematology, Oncology and Stem Cell Transplantation, Kliniken Essen Sued, Essen, Germany
6Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
7Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria
8Hubertus Wald University Cancer Center, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
9Department of Internal Medicine II, University Hospital of Tübingen, Tübingen, Germany
10Department of Internal Medicine II, University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany
11Department of Internal Medicine III, University Hospital Bonn, Bonn, Germany
12III. Department of Medicine, Hematology and Medical Oncology, Technical University of Munich, Munich, Germany
13Department of Internal Medicine III, Municipal Hospital of Karlsruhe, Karlsruhe, Germany
14Department of Hematology and Oncology, Katharinenhospital Stuttgart, Stuttgart, Germany
15Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
16Department of Internal Medicine III, Municipal Hospital of Braunschweig, Braunschweig, Germany

Background: Nucleophosmin (NPM1mut) mutations represent one of the most common gene mutations in acute myeloid leukaemia (AML) and can be used for monitoring minimal residual disease (MRD). In a former study, we could define clinical relevant check-points and a cut-off value to identify patients (pts) at high risk of relapse.

Aims: To confirm our previous results on the clinical relevance of NPM1mut transcript levels (TL) in an extended cohort of younger AML pts (18 to 60 years) harbouring NPM1mut type A, B, C, D, JT, 4, QM, NM or KM, and to assess the impact of concurrent FLT3 internal tandem duplications (ITD) and DNMT3A (DNMT3Amut) mutations on NPM1mut TL kinetics.

Methods: All pts were enrolled in one of four AMLSG [AMLHD98A (n=46; NCT00146120); AMLSG 07-04 (n=199; NCT00151242); AMLSG 09-09 (n=179; NCT00893399); AMLSG 16-10 (n=75; NCT01477606)] treatment trials. Treatment comprised double induction therapy (DI) with ICE (idarubicin, cytarabine, etoposide) with or without ATRA or gemtuzumab ozogamicin, or 1 cycle of daunorubicin and cytarabine followed by 1 to 4 cycles of high-dose cytarabine (n=292), autologous (n=19) or allogeneic stem cell transplantation (n=141). NPM1mut TL (ratio of NPM1mut/ABL1 transcripts x 104) were determined by RQ-PCR using TaqMan technology; the sensitivity of the assays was 10-5 to 10-6. DNMT3A and FLT3-ITD (FLT3-ITDmut) mutation status was assessed by standard PCR-based methods.

Results: A total of 2835 samples from 499 NPM1mut pts were analysed at diagnosis (n=439), after each treatment cycle (n=1394) and during follow-up (FU) (n=1002). Peripheral blood (PB) samples were only included in the advanced FU period (defined as at least 12 months after completion of therapy). NPM1mut TL at diagnosis varied between 7.03 x103 and 2.38 x 107 (median 5.37 x 105). Pretreatment NPM1mut TL were not associated with clinical characteristics (e.g., age, WBC, BM blasts, FLT3-ITDmut, DNMT3Amut) with the exception of LDH level (p=0.006) and did not impact event-free survival (EFS), relapse-free (RFS) and overall survival (OS). NPM1mut TL as log 10 transformed continuous variable at different time points during therapy were significantly associated with shorter remission duration (RD) and shorter OS. After DI therapy, the cumulative incidence of relapse (CIR) at 4 years was 10% for RQ-PCR-negative pts (n=41) versus 45% for RQ-PCR-positive pts (n=226) (p<0.0001); the lower CIR translated into a significant better OS (92% versus 60%, respectively; p=0.001). After completion of therapy, CIR at 4 years was 13% for RQ-PCR-negative pts (n=126) and thus significantly lower compared with 56% in RQ-PCR-positive pts (n=139; p<0.00001). Again, the lower CIR translated into a significantly better OS (81% versus 55%, respectively; p<0.00001). Multivariable analysis performed at both time points showed that NPM1mut TL were significantly associated with a shorter RD (HR, 1.86; 2.30, respectively) and shorter OS (HR, 1.58; 1.72, respectively). During FU, 1002 bone marrow (BM) and PB samples from 280 pts were analysed. The relapse rate at 2 years for pts exceeding the previously defined cut-off value of >200 NPM1mut copies was 90% with a median time to relapse of 1.38 months. In contrast, only 6/104 pts with sustaining RQ-PCR negativity relapsed. Finally, we evaluated the impact of concurrent FLT3-ITDmut and DNMT3Amut on kinetics of NPM1mut TL. Following the first induction cycle, the median NPM1mut TL was significantly lower in pts with the NPM1mut/FLT3-ITDwildtype/DNMT3Awildtype genotype compared to pts with the genotype NPM1mut/FLT3-ITDmut/DNMT3Amut. This effect could be observed throughout subsequent treatment cycles.

Conclusions: The results of our analysis on an extended cohort of younger AML pts with NPM1mut highly confirmed the two clinically relevant MRD check-points, after DI and after completion of therapy; during the FU period, exceeding a cut-off value of >200 TL was highly predictive for relapse. Finally, we found a significant impact of concurrent FLT3-ITDmut/DNMT3Amut on the kinetics of NPM1mut TL.

Disclosures: Fielder: Amgen: Other: Congress Participation ; Teva: Other: Congress Participation ; Kolltan: Research Funding ; Amgen: Research Funding ; Pfizer: Research Funding ; Astellas: Other: Congress Participation . Horst: Boehringer Ingleheim: Research Funding ; MSD: Research Funding ; Pfizer: Research Funding ; Gilead: Honoraria , Research Funding ; Amgen: Honoraria , Research Funding . Götze: Celgene Corp.: Honoraria ; Novartis: Honoraria . Schlenk: Pfizer: Honoraria , Research Funding ; Janssen: Membership on an entity’s Board of Directors or advisory committees ; Teva: Honoraria , Research Funding ; Boehringer-Ingelheim: Honoraria ; Arog: Honoraria , Research Funding ; Novartis: Honoraria , Research Funding ; Daiichi Sankyo: Membership on an entity’s Board of Directors or advisory committees .

*signifies non-member of ASH