Midostaurin plus intensive chemotherapy for younger and older Patients with AML and FLT3 internal tandem duplications

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 -