title: Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation.
abstract: Acute myeloid leukemia (AML) patients with internal tandem duplication (ITD) mutations in the Fms-like tyrosine-3 (FLT3) gene have a dismal prognosis. Here we report compassionate-use results with the multikinase and FLT3-ITD inhibitor sorafenib for the treatment of relapsed or refractory FLT3-ITD-positive AML. Sorafenib induced clinically meaningful and very rapid responses in all 6 patients treated either before (n = 2), after (n = 3), or both before and after (n = 1) allogeneic stem cell transplantation (allo-SCT). Sorafenib-induced remissions facilitated allo-SCT in 2 of the 3 refractory patients. Two of the 4 patients who were treated after allo-SCT survived 216 and 221 days, respectively, whereas the other 2 remain in ongoing complete molecular remission. Sorafenib response was associated with an inhibition of the antiapoptotic FLT3-ITD target Stat-5 in vivo. Together, sorafenib monotherapy before or after allo-SCT has remarkable clinical activity in poor risk FLT3-ITD-positive AML and deserves further evaluation in prospective clinical trials.
authors.affiliation: Philipps University of Marburg, Medical Center of the University Giessen and Marburg, Campus Marburg, Department of Hematology, Oncology and Immunology, Marburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Metzelder
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Ellen
authors.initials: E
authors.lastname: Wollmer
authors.forename: Michael
authors.initials: M
authors.lastname: Wanzel
authors.forename: Sabine
authors.initials: S
authors.lastname: Teichler
authors.forename: Anuhar
authors.initials: A
authors.lastname: Chaturvedi
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.forename: Erich
authors.initials: E
authors.lastname: Enghofer
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Burchert
mesh_terms: D000208:Acute Disease; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004341:Drug Evaluation; D019008:Drug Resistance, Neoplasm; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D012074:Remission Induction; D000077157:Sorafenib; D020080:Tandem Repeat Sequences; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3