title: Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation.
abstract: The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1-42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT.
authors.affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. astrid.plessl@usb.ch.
authors.forename: A
authors.initials: A
authors.lastname: Tschan-Plessl
authors.affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Halter
authors.affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Heim
authors.affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Medinger
authors.affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: J R
authors.initials: JR
authors.lastname: Passweg
authors.affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Gerull
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D000077157:Sorafenib; D020080:Tandem Repeat Sequences / Q000235:genetics; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3
keywords: Allogeneic; Sorafenib; Tyrosine-kinase inhibitor; flt3