MOLECULAR LANDSCAPE AND PROGNOSTIC IMPACT OF FLT3 INTERNAL TANDEM DUPLICATION INSERTION SITE IN ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE RATIFY STUDY (ALLIANCE 10603)
Author(s): ,
Frank G. Rücker
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Ling Du
Affiliations:
Novartis Pharmaceuticals,Basel,Switzerland
,
Tamara J. Blätte
Affiliations:
Department of Hematology, Oncology and Tumor Immunology,Charité University,Berlin,Germany
,
Axel Benner
Affiliations:
Division of Biostatistics,German Cancer Research Center,Heidelberg,Germany
,
Julia Krzykalla
Affiliations:
Division of Biostatistics,German Cancer Research Center,Heidelberg,Germany
,
Insa Gathmann
Affiliations:
Novartis Pharmaceuticals,Basel,Switzerland
,
Richard A. Larson
Affiliations:
Department of Medicine and Comprehensive Cancer Center,University of Chicago,Chicago,United States
,
Maria Teresa Voso
Affiliations:
Department of Biomedicine and Prevention,Università di Roma 'Tor Vergata',Rome,Italy
,
Sergio Amadori
Affiliations:
Department of Biomedicine and Prevention,Università di Roma 'Tor Vergata',Rome,Italy
,
Thomas W. Prior
Affiliations:
The Ohio State University Comprehensive Cancer Center,Columbus,United States
,
Joseph M. Brandwein
Affiliations:
Department of Medicine,University of Alberta,Edmonton,Canada
,
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
,
Michelle Geddes
Affiliations:
University of Calgary,Calgary,Canada
,
Jorge Sierra
Affiliations:
Hematology Department,Hospital de la Santa Creu i Sant Pau and Jose Carreras Leukemia Research Institute, Autonomus University of Barcelona,Barcelona,Spain
,
Celine Pallaud
Affiliations:
Novartis Pharmaceuticals,Basel,Switzerland
,
Miguel Sanz
Affiliations:
Hospital Universitario la Fe, Hematology Department, Department of Medicine,University of Valencia,Valencia,Spain
,
Theo de Witte
Affiliations:
Radboud Institute Molecular Studies,Radboud University Medical Center,Nijmegen,Netherlands
,
Dietger Niederwieser
Affiliations:
Hematology and Oncology,University of Leipzig,Leipzig,Germany
,
Thomas Fischer
Affiliations:
Department of Hematology and Oncology, Center of Internal Medicine,Otto-von-Guericke University Magdeburg,Magdeburg,Germany
,
Gerhard Ehninger
Affiliations:
Medizinische Klinik und Poliklinik I,Universitätsklinikum Carl Gustav Carus der TU Dresden,Dresden,Germany
,
Michael Heuser
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
,
Arnold Ganser
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
,
Lars Bullinger
Affiliations:
Department of Hematology, Oncology and Tumor Immunology,Charité University,Berlin,Germany
,
Clara D. Bloomfield
Affiliations:
The Ohio State University Comprehensive Cancer Center,Columbus,United States
,
Richard M. Stone
Affiliations:
Department of Medical Oncology,Dana-Farber/Partners CancerCare,Boston,United States
,
Hartmut 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
Konstanze Döhner
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
EHA Library. G. Rücker F. 06/12/20; 294968; S148
Dr. Frank G. Rücker
Dr. Frank G. Rücker
Contributions
Abstract

Abstract: S148

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: AML epidemiology and genetics

Background
Internal tandem duplications of the FLT3 gene (FLT3-ITD), present in approximately 25% of newly diagnosed adult AML, are associated with poor prognosis, in particular in cases of high mutant to wild-type allelic ratio (AR) and/or insertion site (IS) in the beta1-sheet.

Aims

To investigate the relationship between ITD IS and patient (pt) outcome.

Methods
Roche 454 next generation sequencing (NGS) was performed in 452/555 (81.4%) FLT3-ITD positive pts enrolled into the RATIFY trial (NCT00651261).

Results

NGS identified 908 ITDs with up to 9 ITDs/pt; 242 (53.5%) pts exhibited ≥2 ITD clones (2 ITDs, 29%; 3 ITDs, 12.8%; 4 ITDs, 5.3%; 5 ITDs, 4%; 6 ITDs, 0.7%; 7 ITDs, 1.5%; 9 ITDs, 0.2%). Median ITD-size was 45 nucleotides (range, 6-246); all ITDs were in-frame with direct head-to-tail orientation. According to the 4 functional domains, 488 ITDs (53.7%) were located within the juxtamembrane domain (JMD), 155 (17.1%) within the hinge region of JMD, 250 (27.5%) within the beta1-sheet, and 15 (1.7%) 3´of beta1-sheet. In the 242 pts featuring multiple ITD clones, 698 concurrent IS were delineated with coexistent integrations within JMD (41.5%) being the most frequent, followed by JMD and beta1-sheet (20.2%), and within beta1-sheet (12.2%). ITD size strongly correlated with IS, in that the more C-terminal the IS, the longer the inserted fragment (P<0.001).

NPM1 mutations (NPM1mut), present in 203/358 pts (56.7%), were positively correlated with IS in JMD (P=0.03) and inversely with IS in the hinge region (P=0.02) and the beta1-sheet (P=0.007).

Complete remission (CR) was achieved in 274/452 (60.6%) pts. The impact of ITD IS on response to induction was assessed in a logistic regression model. ITD IS were categorized in (i) JMD sole (n=251), (ii) JMD and beta1-sheet (n=111), and (iii) beta1-sheet sole (n=75). Co-variables were midostaurin treatment, log2 of NGS-based AR, number of ITDs, log2 of WBC counts, age, and NPM1mut. In this model, number of ITDs (OR, 0.79; P=0.04) and WBC counts (OR, 0.82; P=0.008) predicted lower CR rate, while NPM1mut was favorable for CR achievement (OR, 2.07; P=0.003).

Survival analysis according to categorized IS groups showed that pts exhibiting insertion exclusively in the beta1-sheet had significantly inferior OS (P=0.04) compared to the other 2 groups. In multivariate models for OS and CIR, including allogeneic hematopoietic stem-cell transplantation in first CR (HCT) as time-dependent covariate, consistently unfavorable variables were FLT3-ITD IS in beta1-sheet sole (compared to JMD sole: OS: HR, 1.59; P=0.02; CIR: HR, 2.48; P=0.002; and compared to JMD/beta1-sheet: OS: HR, 2.39; P=0.002; CIR: HR, 1.92; P=0.09) and WBC counts (OS: HR, 1.12; P=0.01; CIR: HR, 1.14; P=0.04), while favorable variables were midostaurin (OS: HR, 0.72; P=0.03; CIR: HR, 0.64; P=0.03) and HCT (OS: HR, 0.50; P<0.001; CIR: HR, 0.45; P=0.002). Cox regression models according to IS revealed HCT as only consistent variable of favorable impact for OS across all 3 IS subgroups. Other variables impacted prognosis only in individual models. Notably, midostaurin was significant only for pts with FLT3-ITD IS in JMD sole (HR, 0.54; P=0.003).

Conclusion

In this cohort of 452 FLT3-ITD mutated AML pts treated within the RATIFY trial the negative prognostic impact of beta1-sheet IS was confirmed. Furthermore, the beneficial effect of additional midostaurin could be validated, in particular for pts with IS in JMD sole. In addition these data further stress the favorable impact of allogeneic HCT.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): AML, Flt3-ITD, Prognosis

Abstract: S148

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: AML epidemiology and genetics

Background
Internal tandem duplications of the FLT3 gene (FLT3-ITD), present in approximately 25% of newly diagnosed adult AML, are associated with poor prognosis, in particular in cases of high mutant to wild-type allelic ratio (AR) and/or insertion site (IS) in the beta1-sheet.

Aims

To investigate the relationship between ITD IS and patient (pt) outcome.

Methods
Roche 454 next generation sequencing (NGS) was performed in 452/555 (81.4%) FLT3-ITD positive pts enrolled into the RATIFY trial (NCT00651261).

Results

NGS identified 908 ITDs with up to 9 ITDs/pt; 242 (53.5%) pts exhibited ≥2 ITD clones (2 ITDs, 29%; 3 ITDs, 12.8%; 4 ITDs, 5.3%; 5 ITDs, 4%; 6 ITDs, 0.7%; 7 ITDs, 1.5%; 9 ITDs, 0.2%). Median ITD-size was 45 nucleotides (range, 6-246); all ITDs were in-frame with direct head-to-tail orientation. According to the 4 functional domains, 488 ITDs (53.7%) were located within the juxtamembrane domain (JMD), 155 (17.1%) within the hinge region of JMD, 250 (27.5%) within the beta1-sheet, and 15 (1.7%) 3´of beta1-sheet. In the 242 pts featuring multiple ITD clones, 698 concurrent IS were delineated with coexistent integrations within JMD (41.5%) being the most frequent, followed by JMD and beta1-sheet (20.2%), and within beta1-sheet (12.2%). ITD size strongly correlated with IS, in that the more C-terminal the IS, the longer the inserted fragment (P<0.001).

NPM1 mutations (NPM1mut), present in 203/358 pts (56.7%), were positively correlated with IS in JMD (P=0.03) and inversely with IS in the hinge region (P=0.02) and the beta1-sheet (P=0.007).

Complete remission (CR) was achieved in 274/452 (60.6%) pts. The impact of ITD IS on response to induction was assessed in a logistic regression model. ITD IS were categorized in (i) JMD sole (n=251), (ii) JMD and beta1-sheet (n=111), and (iii) beta1-sheet sole (n=75). Co-variables were midostaurin treatment, log2 of NGS-based AR, number of ITDs, log2 of WBC counts, age, and NPM1mut. In this model, number of ITDs (OR, 0.79; P=0.04) and WBC counts (OR, 0.82; P=0.008) predicted lower CR rate, while NPM1mut was favorable for CR achievement (OR, 2.07; P=0.003).

Survival analysis according to categorized IS groups showed that pts exhibiting insertion exclusively in the beta1-sheet had significantly inferior OS (P=0.04) compared to the other 2 groups. In multivariate models for OS and CIR, including allogeneic hematopoietic stem-cell transplantation in first CR (HCT) as time-dependent covariate, consistently unfavorable variables were FLT3-ITD IS in beta1-sheet sole (compared to JMD sole: OS: HR, 1.59; P=0.02; CIR: HR, 2.48; P=0.002; and compared to JMD/beta1-sheet: OS: HR, 2.39; P=0.002; CIR: HR, 1.92; P=0.09) and WBC counts (OS: HR, 1.12; P=0.01; CIR: HR, 1.14; P=0.04), while favorable variables were midostaurin (OS: HR, 0.72; P=0.03; CIR: HR, 0.64; P=0.03) and HCT (OS: HR, 0.50; P<0.001; CIR: HR, 0.45; P=0.002). Cox regression models according to IS revealed HCT as only consistent variable of favorable impact for OS across all 3 IS subgroups. Other variables impacted prognosis only in individual models. Notably, midostaurin was significant only for pts with FLT3-ITD IS in JMD sole (HR, 0.54; P=0.003).

Conclusion

In this cohort of 452 FLT3-ITD mutated AML pts treated within the RATIFY trial the negative prognostic impact of beta1-sheet IS was confirmed. Furthermore, the beneficial effect of additional midostaurin could be validated, in particular for pts with IS in JMD sole. In addition these data further stress the favorable impact of allogeneic HCT.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): AML, Flt3-ITD, Prognosis

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