SIGNIFICANT EFFECT OF GEMTUZUMAB OZOGAMICIN ON MEASURABLE RESIDUAL DISEASE AND RISK OF RELAPSE IN PATIENTS WITH NEWLY DIAGNOSED NPM1 MUTATED AML- RESULTS FROM THE AMLSG 09-09 TRIAL
Author(s): ,
Silke Kapp-Schwoerer
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Daniela Weber
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Andrea Corbacioglu
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Verena I. Gaidzik
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Peter Paschka
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Jan Krönke
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Frauke Theis
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Frank G. Rücker
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Maria-Veronica Teleanu
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Ekaterina Panina
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Nikolaus Jahn
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Julia K. Herzig
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Lena Kubanek
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Anika Schrade
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Gudrun Göhring
Affiliations:
Department of Human Genetics,Hannover Medical School,Hannover ,Germany
,
Walter Fiedler
Affiliations:
Hubertus Wald University Cancer Center, University Medical Centre Hamburg-Eppendorf,Hamburg,Germany
,
Thomas Kindler
Affiliations:
Department of Hematology, Medical Oncology & Pneumology,University Cancer Center Mainz,Mainz,Germany
,
Thomas Schroeder
Affiliations:
Department of Hematology, Oncology, and Clinical Immunology,Heinrich-Heine-University Düsseldorf,Düsseldorf,Germany
,
Karin Tina Mayer
Affiliations:
Department of Hematology, Oncology,University Hospital Bonn,Bonn,Germany
,
Michael Lübbert
Affiliations:
Department of Medicine I, Medical Center,Faculty of Medicine, University of Freiburg,Freiburg,Germany
,
Mohammed Wattad
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,Kliniken Essen Süd,Essen,Germany
,
Katharina S. Götze
Affiliations:
III. Department of Medicine, Hematology and Medical Oncology,Technical University of Munich,Munich,Germany
,
Heinz A. Horst
Affiliations:
Department of Internal Medicine II,University Hospital Schleswig Holstein,Kiel,Germany
,
Elisabeth Koller
Affiliations:
III. Department of Medicine, Hematology and Medical Oncology,Hanuschkrankenhaus Wien,Wien,Austria
,
Gerald Wulf
Affiliations:
Department of Hematology and Oncology,Georg-August-University Göttingen,Göttingen,Germany
,
Jan Schleicher
Affiliations:
Department of Hematology and Oncology,Katharinenhospital Stuttgart,Stuttgart,Germany
,
Martin Bentz
Affiliations:
Department of Internal Medicine III,Municipal Hospital of Karlsruhe,Karlsruhe,Germany
,
Jürgen Krauter
Affiliations:
Department of Internal Medicine III,Municipal Hospital of Braunschweig,Braunschweig,Germany
,
Lars Bullinger
Affiliations:
Department of Hematology, Oncology and Tumorimmunology,Charité University Medicine Berlin, Campus Virchow Klinikum,Berlin,Germany
,
Julia Krzykalla
Affiliations:
Division of Biostatistics,German Cancer Research Center,Heidelberg,Germany
,
Axel Benner
Affiliations:
Division of Biostatistics,German Cancer Research Center,Heidelberg,Germany
,
Richard F. Schlenk
Affiliations:
Nationales Centrum für Tumorerkrankungen Trial Center, National Center of Tumor Diseases,German Cancer Research Center,Heidelberg,Germany;Department of Internal Medicine V,Heidelberg University Hospital,Heidelberg,Germany
,
Felicitas Thol
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,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
,
Hartmut Döhner
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
Konstanze Döhner
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
EHA Library. Kapp-Schwoerer S. 06/12/20; 294361; EP442
Silke Kapp-Schwoerer
Silke Kapp-Schwoerer
Contributions
Abstract

Abstract: EP442

Type: e-Poster

Presentation during EHA25: All e-Poster 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.

Background
Measurable residual disease (MRD) monitoring in Nucleophosmin1 mutated (NPM1mut) patients (pts) with acute myeloid leukemia (AML) is of significant clinical relevance and provides a powerful tool to evaluate the effects of novel therapies within clinical trials.

Aims

To determine the impact of NPM1mut MRD and to assess the effect of the anti-CD33 immunotoxin gemtuzumab-ozogamicin (GO) on the kinetics of NPM1mut transcript levels (TL) in pts with newly diagnosed NPM1mut AML enrolled in the Phase III AMLSG 09-09 trial (NCT00893399) [n=588; 18 to 82 years (yrs)].

Methods

For this companion MRD study, 469 pts in complete remission (CR) or CR with incomplete blood count recovery after two induction cycles with at least one subsequent bone marrow (BM) or peripheral blood (PB) sample were eligible. Standard treatment comprised two induction cycles of A-ICE (ATRA, idarubicin, cytarabine, etoposide; arm A; n=237) followed by up to three cycles of high-dose cytarabine as post-remission therapy in the majority of pts (n=394, 84%). In this trial, GO was randomized (1:1) to standard therapy. In the investigational arm (arm B; n=232), GO (3 mg/m²) was given at d1 of each induction and the first consolidation cycle. NPM1mut TL (ratio of NPM1mut/ABL1 transcripts x 104) were determined by RQ-PCR (sensitivity 10-5 to 10-6).

Results

In total, we analyzed 3733 BM and 3793 PB samples. Both study arms were well balanced with regard to pts` characteristics. After two treatment cycles, the 4-yr cumulative incidence of relapse (CIR) was significantly lower for pts achieving a ≥3 log10 reduction of NPM1mut TL or MRD negativity (MRD negative vs. positive: BM: 25.3% vs 37.9%, P=.03; PB: 18.4% vs 53.4%, P<.001). Same results were found at end of treatment (EOT).
Focusing on treatment effects, the median NPM1mut TL were lower in arm B across all treatment cycles, resulting in a significantly higher proportion of pts achieving MRD negativity at EOT (BM: 56% vs 41%; P=.01; PB: 85% vs 72%; P=.02). In pts with detectable NPM1mut TL in BM after two treatment cycles, the 4-yr CIR was significantly lower in arm B (29.3% vs 45.7%; P=.009) which is mainly due to the better reduction of NPM1mut TL after each subsequent treatment cycle. In multivariate analyses after two treatment cycles and at EOT, MRD persistence, concurrent DNMT3Amut, and higher age revealed as significant prognostic factors for higher relapse risk, in both BM and PB. During follow-up (FU), more pts in arm B showed sustained MRD negativity (BM: 41% vs 30%, P=.06; PB: 51% vs 39%, P=.05). Our previously defined cut-off value of ≥200 NPM1mut TL was highly predictive for relapse. However, neither the 4-yr CIR for pts with NPM1mut TL ≥200 (BM: 61% vs 71%; PB: 69% vs 71%) nor the median time to relapse was influenced by the addition of GO.
We further addressed the NPM1mut-DNMT3Amut interaction in BM. Pts without concurrent DNMT3Amut had a better clearance of NPM1mut TL leading to a higher proportion of pts achieving MRD negativity (after two cycles: 19.0% vs 8.3%; P=.02; EOT: 52.1% vs 36%; P=.04) and a superior 4-yr CIR indicating that concurrent DNMT3Amut may confer resistance to therapy in NPM1mut AML.

Conclusion

MRD monitoring of NPM1mut TL is a powerful tool to identify pts at an increased risk of relapse. The addition of GO to intensive chemotherapy resulted in a significantly better reduction of NPM1mut TL and consequently in a higher proportion of pts achieving MRD negativity which was associated with a significantly lower CIR rate.

Session topic: 03. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Acute myeloid leukemia, Minimal residual disease (MRD), Therapy

Abstract: EP442

Type: e-Poster

Presentation during EHA25: All e-Poster 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.

Background
Measurable residual disease (MRD) monitoring in Nucleophosmin1 mutated (NPM1mut) patients (pts) with acute myeloid leukemia (AML) is of significant clinical relevance and provides a powerful tool to evaluate the effects of novel therapies within clinical trials.

Aims

To determine the impact of NPM1mut MRD and to assess the effect of the anti-CD33 immunotoxin gemtuzumab-ozogamicin (GO) on the kinetics of NPM1mut transcript levels (TL) in pts with newly diagnosed NPM1mut AML enrolled in the Phase III AMLSG 09-09 trial (NCT00893399) [n=588; 18 to 82 years (yrs)].

Methods

For this companion MRD study, 469 pts in complete remission (CR) or CR with incomplete blood count recovery after two induction cycles with at least one subsequent bone marrow (BM) or peripheral blood (PB) sample were eligible. Standard treatment comprised two induction cycles of A-ICE (ATRA, idarubicin, cytarabine, etoposide; arm A; n=237) followed by up to three cycles of high-dose cytarabine as post-remission therapy in the majority of pts (n=394, 84%). In this trial, GO was randomized (1:1) to standard therapy. In the investigational arm (arm B; n=232), GO (3 mg/m²) was given at d1 of each induction and the first consolidation cycle. NPM1mut TL (ratio of NPM1mut/ABL1 transcripts x 104) were determined by RQ-PCR (sensitivity 10-5 to 10-6).

Results

In total, we analyzed 3733 BM and 3793 PB samples. Both study arms were well balanced with regard to pts` characteristics. After two treatment cycles, the 4-yr cumulative incidence of relapse (CIR) was significantly lower for pts achieving a ≥3 log10 reduction of NPM1mut TL or MRD negativity (MRD negative vs. positive: BM: 25.3% vs 37.9%, P=.03; PB: 18.4% vs 53.4%, P<.001). Same results were found at end of treatment (EOT).
Focusing on treatment effects, the median NPM1mut TL were lower in arm B across all treatment cycles, resulting in a significantly higher proportion of pts achieving MRD negativity at EOT (BM: 56% vs 41%; P=.01; PB: 85% vs 72%; P=.02). In pts with detectable NPM1mut TL in BM after two treatment cycles, the 4-yr CIR was significantly lower in arm B (29.3% vs 45.7%; P=.009) which is mainly due to the better reduction of NPM1mut TL after each subsequent treatment cycle. In multivariate analyses after two treatment cycles and at EOT, MRD persistence, concurrent DNMT3Amut, and higher age revealed as significant prognostic factors for higher relapse risk, in both BM and PB. During follow-up (FU), more pts in arm B showed sustained MRD negativity (BM: 41% vs 30%, P=.06; PB: 51% vs 39%, P=.05). Our previously defined cut-off value of ≥200 NPM1mut TL was highly predictive for relapse. However, neither the 4-yr CIR for pts with NPM1mut TL ≥200 (BM: 61% vs 71%; PB: 69% vs 71%) nor the median time to relapse was influenced by the addition of GO.
We further addressed the NPM1mut-DNMT3Amut interaction in BM. Pts without concurrent DNMT3Amut had a better clearance of NPM1mut TL leading to a higher proportion of pts achieving MRD negativity (after two cycles: 19.0% vs 8.3%; P=.02; EOT: 52.1% vs 36%; P=.04) and a superior 4-yr CIR indicating that concurrent DNMT3Amut may confer resistance to therapy in NPM1mut AML.

Conclusion

MRD monitoring of NPM1mut TL is a powerful tool to identify pts at an increased risk of relapse. The addition of GO to intensive chemotherapy resulted in a significantly better reduction of NPM1mut TL and consequently in a higher proportion of pts achieving MRD negativity which was associated with a significantly lower CIR rate.

Session topic: 03. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Acute myeloid leukemia, Minimal residual disease (MRD), Therapy

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies