Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD

Richard F. Schlenk, Daniela Weber, Walter Fiedler, Helmut R. Salih, Gerald Wulf, Hans Salwender, Thomas Schroeder, Thomas Kindler, Michael Lübbert, Dominik Wolf, Jörg Westermann, Doris Kraemer, Katharina S. Götze, Heinz-August Horst, Jürgen Krauter, Michael Girschikofsky, Mark Ringhoffer, Thomas Südhoff, Gerhard Held, Hans-Günter Derigs, Roland Schroers, Richard Greil, Martin Grießhammer, Elisabeth Lange, Alexander Burchardt, Uwe Martens, Bernd Hertenstein, Lore Marretta, Michael Heuser, Felicitas Thol, Verena I. Gaidzik, Wolfgang Herr, Julia Krzykalla, Axel Benner, Konstanze Döhner, Arnold Ganser, Peter Paschka and Hartmut Döhner on behalf of the German-Austrian AML Study Group

Key Points

  • Midostaurin plus intensive chemotherapy can be safely administered in older FLT3-ITD-positive patients with AML.

  • Compared with historical controls, midostaurin significantly improved event-free survival in older and younger FLT3-ITD positive patients with AML.


Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at as #NCT01477606.

  • Submitted August 13, 2018.
  • Accepted November 24, 2018.
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