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.

Keywords: Acute myeloid leukemia; Allogeneic stem cell transplantation; Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD); Maintenance; Sorafenib.

Conflict of interest statement

Disclosures/COI: The remaining authors report no relevant conflicts of interest.

Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

PFS and OS for all patients (n=22) and for patients in CR1/CR2 (n=19)

Figure 2

A. Plasma inhibitory activity (PIA) assay of a patient treated with 200 mg twice daily sorafenib. B = baseline; D = treatment day (e.g., C1D8 = Day 8 of cycle 1); M3 = Cycle 3; M6 = Cycle 6. B. PIA results (expressed as % P-FLT3 at baseline) plotted against plasma sorafenib levels measured from the same time points. The color of the dot denotes the sorafenib dose the patient was receiving at the time of the measurement (not the original cohort assigned). Black dots = 200 mg twice daily; red dots = 400 mg in the AM, 200 mg in the PM; blue dots = 400 mg twice daily. Note that several patients had multiple samples represented at different time points.

Figure 3

Pharmacokinetics of sorafenib and N-oxide. Plasma concentrations of sorafenib and N-oxide were measured at several time points. Note that several patients had multiple samples represented at different time points.

Figure 4

Plasma levels of FLT3 ligand in patients treated with sorafenib. (p =0.016 comparing baseline to day 28 levels)