Midostaurin plus intensive chemotherapy for younger and older Patients with AML and FLT3 internal tandem duplications
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Midostaurin plus intensive chemotherapy for younger and older Patients with AML and FLT3 internal tandem duplications. / Döhner, Hartmut; Weber, Daniela; Krzykalla, Julia; Fiedler, Walter; Wulf, Gerald Georg; Salih, Helmut R; Lübbert, Michael; Kühn, Michael; Schroeder, Thomas; Salwender, Hans; Götze, Katharina S; Westermann, Jörg; Fransecky, Lars; Mayer, Karin; Hertenstein, Bernd; Ringhoffer, Mark; Tischler, Hans-Joachim; Machherndl-Spandl, Sigrid; Schrade, Anika; Paschka, Peter; Gaidzik, Verena I; Theis, Frauke; Thol, Felicitas R; Heuser, Michael; Schlenk, Richard F; Bullinger, Lars; Saadati, Maral; Benner, Axel; Larson, Richard A; Stone, Richard M; Döhner, Konstanze; Ganser, Arnold; German-Austrian AML Study Group (AMLSG).
In: BLOOD ADV, Vol. 6, No. 18, 27.09.2022, p. 5345-5355.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Midostaurin plus intensive chemotherapy for younger and older Patients with AML and FLT3 internal tandem duplications
AU - Döhner, Hartmut
AU - Weber, Daniela
AU - Krzykalla, Julia
AU - Fiedler, Walter
AU - Wulf, Gerald Georg
AU - Salih, Helmut R
AU - Lübbert, Michael
AU - Kühn, Michael
AU - Schroeder, Thomas
AU - Salwender, Hans
AU - Götze, Katharina S
AU - Westermann, Jörg
AU - Fransecky, Lars
AU - Mayer, Karin
AU - Hertenstein, Bernd
AU - Ringhoffer, Mark
AU - Tischler, Hans-Joachim
AU - Machherndl-Spandl, Sigrid
AU - Schrade, Anika
AU - Paschka, Peter
AU - Gaidzik, Verena I
AU - Theis, Frauke
AU - Thol, Felicitas R
AU - Heuser, Michael
AU - Schlenk, Richard F
AU - Bullinger, Lars
AU - Saadati, Maral
AU - Benner, Axel
AU - Larson, Richard A
AU - Stone, Richard M
AU - Döhner, Konstanze
AU - Ganser, Arnold
AU - German-Austrian AML Study Group (AMLSG)
N1 - Copyright © 2022 American Society of Hematology.
PY - 2022/9/27
Y1 - 2022/9/27
N2 - We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.
AB - We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.
U2 - 10.1182/bloodadvances.2022007223
DO - 10.1182/bloodadvances.2022007223
M3 - SCORING: Journal article
C2 - 35486475
VL - 6
SP - 5345
EP - 5355
JO - BLOOD ADV
JF - BLOOD ADV
SN - 2473-9529
IS - 18
ER -