title: Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia.
abstract: The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is associated with a high relapse rate for patients with acute myeloid leukemia (AML) even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor, which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.govNCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3 + 3 cohort design was used to define the maximum tolerated dose (MTD), with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT and continued for 12 28-day cycles. Twenty-two patients were enrolled (status at HSCT: first complete remission [CR1], n = 16; second complete remission [CR2], n = 3; refractory, n = 3). The MTD was established at 400 mg twice daily with 1 dose-limiting toxicity (DLT) observed (pericardial effusion). Two patients died of transplantation-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped because of attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1 to 35.0). There was 1 case of grade II acute graft-versus-host disease (GVHD) after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% confidence interval [CI], 21% to 56%). For all patients, 1-year progression-free survival (PFS) was 85% (90% CI, 66% to 94%) and 1-year overall survival (OS) was 95% (90% CI, 79% to 99%) after HSCT. For patients in CR1/CR2 before HSCT (n = 19), 1-year PFS was 95% (90% CI, 76% to 99%) and 1-year OS was 100%, with only 1 patient who relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse.
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: ychen6@partners.org.
authors.forename: Yi-Bin
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Shuli
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Christine
authors.initials: C
authors.lastname: Connolly
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Candice
authors.initials: C
authors.lastname: Del Rio
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Betsy
authors.initials: B
authors.lastname: Valles
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Morgan
authors.initials: M
authors.lastname: Curtis
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Karen
authors.initials: K
authors.lastname: Ballen
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Bimalangshu R
authors.initials: BR
authors.lastname: Dey
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Areej
authors.initials: A
authors.lastname: El-Jawahri
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Amir T
authors.initials: AT
authors.lastname: Fathi
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Amy
authors.initials: A
authors.lastname: Joyce
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: McAfee
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rudek
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Trivikram
authors.initials: T
authors.lastname: Rajkhowa
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Sigitas
authors.initials: S
authors.lastname: Verselis
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Spitzer
authors.affiliation: Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Center, Boston, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Soiffer
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000401:mortality / Q000628:therapy; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000628:therapy; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D012074:Remission Induction; D000077157:Sorafenib; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia; Allogeneic stem cell transplantation; Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD); Maintenance; Sorafenib