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692 Midostaurin Plus Intensive Chemotherapy for Younger and Older Patients with Acute Myeloid Leukemia and FLT3 Internal Tandem DuplicationsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Current approach to FLT3 mutated AML
Hematology Disease Topics & Pathways:
Clinical Trials, Adults, AML, Non-Biological, Clinical Research, Chemotherapy, Elderly, Clinically Relevant, Diseases, Therapies, Myeloid Malignancies, Young Adults, Study Population
Monday, December 13, 2021: 4:00 PM

Hartmut Döhner, MD1, Daniela Weber, MSc1*, Julia Krzykalla, PhD2*, Walter Fiedler, MD3, Gerald Wulf, MD4*, Helmut R. Salih5, Michael Lübbert6*, Michael W.M. Kühn, MD7*, Thomas Schroeder8*, Hans Salwender, MD9*, Katharina S. Götze10*, Jörg Westermann, MD, PhD11*, Lars Fransecky, MD12*, Karin Mayer, MD13*, Bernd Hertenstein, MD14*, Mark Ringhoffer, MD15*, Hans-Joachim Tischler, MD16*, Sigrid Machherndl-Spandl, MD17*, Anika Schrade, PhD18*, Peter Paschka, MD18, Verena I Gaidzik, MD19, Frauke Theis, MD20*, Felicitas R Thol, MD21, Michael Heuser, MD22, Richard F. Schlenk, MD23, Lars Bullinger, MD24, Maral Saadati, PhD25*, Axel Benner, PhD2*, Konstanze Döhner18* and Arnold Ganser, MD22

1Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
2Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4Department of Hematology and Oncology, Georg-August-University of Göttingen, Göttingen, Germany
5Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Tuebingen, Germany
6Department of Internal Medicine I, University Medical Center Freiburg, Freiburg, Germany
7Department of Hematology, Oncology and Pneumology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
8Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany
9Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany
10Department of Medicine III, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany
11Charité-University Medical Center Berlin, Campus Virchow Clinic, Berlin, Germany
12Department of Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Germany
13Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany
14Department of Internal Medicine I, Klinikum Bremen Mitte, Bremen, Germany
15Department of Internal Medicine III, Municipal Hospital of Karlsruhe, Karlsruhe, Germany
16Mühlenkreiskliniken, Minden, Germany
171st Medical Department, Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz GmbH Elisabethinen, Linz, Austria
18Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
19Internal Medicine III, Internal Medicine III, Ulm, Germany
20Department of Internal Medicine III, University Hospital of Ulm, Ulm, Baden-Württemberg, Germany
21Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hanover, Germany
22Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
23University Hospital of Ulm, Ulm, Germany
24Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany
25Saadati Solutions, Ladenburg, Germany

BACKGROUND: Midostaurin is a first-generation, type I multi-targeted kinase inhibitor with inhibitory activity against FLT3-ITD and -TKD mutations. Midostaurin is approved by FDA and EMA in combination with intensive induction and consolidation chemotherapy for adult patients with AML exhibiting an activating FLT3 mutation; the EMA label also includes single-agent maintenance therapy following consolidation chemotherapy. We conducted a phase-II trial (AMLSG 16-10) to evaluate midostaurin with induction chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a one-year midostaurin maintenance therapy in younger and older patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (ITD).

METHODS: Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free (EFS) and overall survival (OS); results were compared to those of a historical control cohort of 415 patients with FLT3-ITD AML. Statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Major differences in trial design compared to the pivotal CALGB 10603/RATIFY trial were: i) only AML with FLT3-ITD were eligible; ii) AML with FLT3 tyrosine kinase domain mutations (only) and core-binding factor AML were not eligible; iii) older patients 60-70 years of age were eligible; iv) all patients were assigned to allogeneic HCT; v) a one-year maintenance treatment with midostaurin was included also after allogeneic HCT; vi) a continuous dosing schedule of midostaurin was applied with the aim to achieve a better target inhibition.

Results: The trial accrued 440 patients, including 312 younger (18-60 yrs) and 128 older (61-70 yrs) patients. Complete remission (CR)/CR with incomplete hematologic recovery rate, median EFS and OS of the 440 patients were 74.9%, 13.6 and 36.2 months, respectively. Multivariate analysis of EFS showed a highly significant hazard reduction for an event for patients treated within AMLSG 16-10 trial compared to the historical controls (HR 0.55; 95%-confidence interval [CI], 0.47, 0.65; P<0.001); this effect was significant in the younger (HR 0.59; 95%-CI, 0.49, 0.71; P<0.001) and the older patient cohort (HR 0.42; 95%-CI, 0.30, 0.60; P<0.001). Multivariate analysis also showed a highly significant beneficial effect on OS (HR 0.57; 95%-CI, 0.47, 0.68; P<0.001), again for both age subgroups. Allogeneic HCT in first CR/CRi was performed according to protocol in 199 of 440 (45%) patients (48% and 38% in younger and older patients, respectively), and an additional 60 patients received allogeneic HCT in firstline therapy (n=33 pts. in CR/CRi after salvage therapy and 27 pts. with active disease); the treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT (n=259) as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients.

Conclusions: In comparison to a historical control cohort, the addition of midostaurin to intensive therapy led to a significant improvement in EFS and OS in both younger and older adult patients with AML and FLT3-ITD.

Figure: Survival distribution for the primary endpoint event-free survival (EFS) and key secondary endpoint overall survival (OS) according to study population and age group.

A EFS by cohort and age group (≤60 versus >60 years)

B OS by cohort and age group (≤60 versus >60 years)

Disclosures: Döhner: Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ulm University Hospital: Current Employment. Fiedler: Servier: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; MorphoSys: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Celgene: Consultancy, Honoraria; Ariad/Incyte: Honoraria; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Wulf: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Salih: BMS: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Synimmune GmbH: Honoraria; Novartis: Honoraria. Lübbert: Imago BioSciences: Honoraria; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Syros: Honoraria; Aristopharm: Research Funding; Cheplapharm: Research Funding; Janssen: Research Funding; Teva: Research Funding; Hexal: Honoraria; Astex: Honoraria; Abbvie: Honoraria. Kühn: Abbvie: Honoraria; Kura Oncology: Honoraria, Research Funding; Pfizer: Honoraria. Schroeder: Abbvie: Honoraria; Astellas: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Pfizer: Honoraria. Salwender: Oncopeptides: Honoraria; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Chugai: Honoraria; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria. Götze: Abbvie: Honoraria; Celgene/BMS: Honoraria, Research Funding. Westermann: Amgen: Consultancy, Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Astellas: Honoraria. Fransecky: Abbvie: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Medac: Honoraria. Mayer: Novartis: Other: Travel support; Celgene: Other: Travel support; Roche: Other: Travel support; Amgen: Other: Travel support; BMS: Other: Travel support; Pfizer: Other: Travel support; Jazz: Other: Travel support; Astellas: Other: Travel support. Hertenstein: Sanofi: Honoraria; Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria. Tischler: AstraZeneca: Other: Travel support; Novartis: Other: Travel support; Janssen: Honoraria; GSK: Other: Travel support; Sanofi-Aventis: Other: Travel support; Abbvie: Other: Travel support. Paschka: Abbvie: Honoraria, Other: Travel support; Agios: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Astex: Honoraria; Celgene: Honoraria, Other: Travel support; Jazz: Honoraria; Novartis: Honoraria, Other: Travel support; Otsuka: Honoraria; Pfizer: Honoraria; Sunesis: Honoraria; BMS: Other, Speakers Bureau; Celgene: Honoraria; Janssen: Other; Takeda: Other. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thol: Novartis: Honoraria; Jazz: Honoraria; BMS/Celgene: Honoraria, Research Funding; Astellas: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Schlenk: Astellas: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Hexal: Honoraria; Neovio Biotech: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Honoraria; Agios: Honoraria. Bullinger: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Astellas: Honoraria; Bristol-Myers Squibb / Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Roche: Honoraria; Daiichi Sankyo: Honoraria; Agios: Research Funding; Astex: Research Funding; Astellas: Research Funding. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria.

OffLabel Disclosure: Midostaurin as single-agent maintenance therapy following allogeneic hematopoietic cell transplantation

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