PROGNOSTIC AND PREDICTIVE IMPACT OF NPM1/FLT3-ITD GENOTYPES AS DEFINED BY 2017 EUROPEAN LEUKEMIANET RISK CATEGORIZATION FROM AML PATIENTS TREATED WITHIN THE INTERNATIONAL RATIFY STUDY
Author(s): ,
Konstanze Döhner
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Christian Thiede
Affiliations:
Medizinische Klinik und Poliklinik I,Universitätsklinikum Carl Gustav Carus der TU Dresden,Dresden,Germany
,
Nikolaus Jahn
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Panina Ekaterina
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Agnes Gambietz
Affiliations:
Division of Biostatistics,German Cancer Research Center,Heidelberg,Germany
,
Thomas W. Prior
Affiliations:
The Ohio State University Comprehensive Cancer Center,Ohio State University,Columbus,United States
,
Guido Marcucci
Affiliations:
City of Hope Comprehensive Cancer,Duarte,United States
,
Daniel Jones
Affiliations:
Department of Pathology,The Ohio State University and James Cancer Hospital,Columbus, OH,United States
,
Jürgen Krauter
Affiliations:
Department Hematology and Oncology,Braunschweig Municipal Hospital,Braunschweig,Germany
,
Heuser Michael
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
,
Francesco Lo-Coco
Affiliations:
Department of Biomedicine and Prevention,Università di Roma 'Tor Vergata',Rome,Italy
,
Tiziana Ottone
Affiliations:
Department of Biomedicine and Prevention,University of Tor Vergata,Rome,Italy
,
Josep Nomdedeu
Affiliations:
Clinical Hematology Service,Hospital de la Santa Creu i Sant Pau,Barcelona,Spain
,
Sumithra J Mandrekar
Affiliations:
Alliance Statistics and Data Center,Mayo Clinic,Rochester,United States
,
Luke Huebner
Affiliations:
Alliance Statistics and Data Center,Mayo Clinic,Rochester,United States
,
Kristina M. Laumann
Affiliations:
Alliance Statistics and Data Center,Mayo Clinic,Rochester,United States
,
Susan M. Geyer
Affiliations:
Health Informatics Institute,University of South Florida,Tampa,United States
,
Rebecca B. Klisovic
Affiliations:
Department of Hematology and Medical Oncology,Emory University,Atlanta,United States
,
Andrew Wei
Affiliations:
Malignant Haematology and Stem Cell Transplantation Service,Alfred Hospital,Melbourne,Australia
,
Jorge Sierra
Affiliations:
Hematology Department,Hospital Santa Creu i Sant Pau,Barcelona,Spain
,
Miguel A. Sanz
Affiliations:
Department of Hematology,Hospital Universitari i Politecnic La Fe, Department of Medicine,University of Valencia,Spain
,
Joseph M. Brandwein
Affiliations:
Department of Medical Oncology and Hematology,Princess Margaret Hospital,Toronto,Canada
,
Theo M. de Witte
Affiliations:
Department of Tumor Immunology,Nijmegen Centre of Life Sciences,Radboud University Nijmegen,Nijmegen,Netherlands
,
Joop H. Jansen
Affiliations:
Department of Laboratory Medicine, Laboratory of Hematology,Radboud University,Nijmegen,Netherlands
,
Dietger Niederwieser
Affiliations:
Division of Hematology and Oncology,University Hospital Leipzig,Leipzig,Germany
,
Frederick R. Appelbaum
Affiliations:
Clinical Research Division,Fred Hutchinson Cancer Research Center,Seattle,United States
,
Bruno C. Medeiros
Affiliations:
Division of Hematology-Oncology, Stanford Comprehensive Cancer Center,Stanford University,Stanford,United States
,
Martin S. Tallman
Affiliations:
Leukemia Service, Department of Medicine,Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College,New York,United States
,
Richard F. Schlenk
Affiliations:
National Center of Tumor Diseases,German Cancer Research Center,Heidelberg,Germany
,
Arnold Ganser
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
,
Hubert Serve
Affiliations:
Department of Medicine II, Hematology/Oncology,Goethe University, Frankfurt/Main,Germany
,
Gerhard Ehninger
Affiliations:
Medizinische Klinik und Poliklinik I,Universitätsklinikum Carl Gustav Carus der TU Dresden,Dresden,Germany
,
Sergio Amadori
Affiliations:
Department of Biomedicine and Prevention,Università di Roma 'Tor Vergata',Rome,Italy
,
Insa Gathmann
Affiliations:
Novartis Pharmaceuticals,Basel,Switzerland
,
Benner Axel
Affiliations:
Division of Biostatistics,German Cancer Research Center,Heidelberg,Germany
,
Celine Pallaud
Affiliations:
Novartis Pharmaceuticals,Basel,Switzerland
,
Richard A. Larson
Affiliations:
Department of Medicine and Comprehensive Cancer Center,University of Chicago,Chicago, IL,United States
,
Richard M. Stone
Affiliations:
Department of Medical Oncology,Dana-Farber/Partners CancerCare,Boston, MA,United States
,
Hartmut Döhner
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
Clara D. Bloomfield
Affiliations:
The Ohio State University Comprehensive Cancer Center,Columbus, OH,United States
EHA Library. Döhner K. Jun 14, 2019; 266060; PF260
Konstanze Döhner
Konstanze Döhner
Contributions
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Abstract

Abstract: PF260

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background
Patients (pts) with AML harboring FLT3 internal tandem duplications (ITD) have poor outcomes, in particular pts with a high ITD mutant to wild-type (wt) allelic ratio (AR; ≥0.5). The 2017 update of the European LeukemiaNet (ELN) recommendations addressed the importance of the ITD AR in the genetic risk stratification and defined distinct NPM1/FLT3-ITD genotypes.

Aims

In this exploratory post-hoc analysis from randomized pts treated within the RATIFY trial evaluating the addition of midostaurin to standard chemotherapy, we investigated the prognostic impact of the NPM1/FLT3-ITD genotypes according to the 2017 ELN risk categories.

Methods

In total, 319 of 717 pts with FLT3-ITD positive AML were included who gave informed consent for biomarker analyses and who could be categorized according to 2017 ELN genetic risk stratification. Median age was 47.9 years (range, 18-60); median follow-up time was 4.8 years.

Results

Pts were categorized as follows: (i) favorable-risk (n=85), NPM1mut/FLT3-ITDlow, irrespective of secondary chromosome abnormalities and concurrent gene mutations; (ii) intermediate-risk (n=111), NPM1mut/FLT3-ITDhigh and NPM1wt/FLT3-ITDlow, both subgroups without adverse cytogenetics and without concurrent RUNX1, ASXL1, TP53 mutations; (iii) adverse-risk (n=123), NPM1wt/FLT3-ITDhigh; as well as NPM1mut/FLT3-ITDhigh and NPM1wt/FLT3-ITDlow with adverse-risk cytogenetic and/or molecular markers; frequencies of RUNX1, ASXL1, and TP53 mutations in adverse-risk AML were 29.2%, 19.8%, and 1.9%, respectively. Rates of allogeneic transplantation (alloSCT) in first complete remission (CR) were not different among the groups, with 29.4%, 35.1%, and 35.0% in pts. with favorable-, intermediate-, and adverse-risk AML, respectively. Rates of CR (including responses after induction 1 and 2) were negatively associated with adverse-risk genetics (51.2% vs 69.4% and 64.0% in favorable- and intermediate-risk, respectively; p=0.02); multivariable logistic regression analysis revealed adverse-risk as significantly different compared to favorable-risk (odds ratio [OR] 0.534, 95% confidence interval [CI] 0.287-0.979; p=0.044), whereas no difference was seen between the two other risk groups; treatment with midostaurin had no impact (p=0.32). Overall survival (OS) differed among the 3 ELN-risk groups; 5-year survival rates were 63%, 43%, 33% for favorable, intermediate- and adverse-risk groups, respectively. The OS curves did not show differential effects of midostaurin among the 3 risk groups (Figure 1), with a benefical effect seen for midostaurin vs placebo in all 3 groups with hazard ratios (HR) estimated as HR=0.52, HR=0.51, and HR=0.55 for favorable-, intermediate-, and adverse-risk groups, respectively. A multivariable Cox model adjusted for age, WBC, sex, and bone marrow blasts was used to test the effects of treatment and risk classification. The resulting model revealed an increasing HR with increasing risk category (p<0.001; intermediate vs. favorable, HR=1.70, 95% CI 1.08-2.68; adverse vs. favorable risk, HR=2.48, 95% CI 1.59-3.86), while treatment with midostaurin significantly reduced risk compared to placebo (p<0.001; HR=0.53, 95% CI 0.38-0.72).

Conclusion

Data from this post-hoc exploratory analysis confirm the prognostic value of the 2017 ELN risk categories also among AML pts with the distinct NPM1/FLT3-ITD genotypes. A Cox model revealed a significant effect for midostaurin compared to placebo independent of the ELN risk groups. Analysis with regard to potential confounding effects of allogenic transplantation are ongoing.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AML, Flt3 inhibitor, Flt3-ITD, Prognostic factor

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