Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation.

BACKGROUND: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. FINDINGS: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. INTERPRETATION: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT.

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses.

Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P=0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

Acetylcholine concentrations and turnover in rat brain structures during anesthesia with halothane, enflurane, and ketamine.

Acetylcholine and choline concentrations in brain structures of rats during anesthesia with halothane (0.7-1.0 per cent inspired), enflurane (2.7-3.0 per cent, inspired) and ketamine (40 mg/kg, iv) were measured by gas chromatography. The turnover rate (biosynthesis) of acetylcholine in vivo was estimated by infusing phosphoryl(Me-14C)choline intravenously, determining specific activities of choline and acetylcholine, and applying principles of steady-state kinetics to compute the fractional rate constant of acetylcholine. Acetylcholine concentrations in brain structures did not change during anesthesia. Halothane decreased the acetylcholine turnover rates in all parts of the brain. Enflurane decreased the acetylcholine turnover rate in the cerebral cortex only, but not in the caudate nucleus, the hippocampus, and the hypothalamic and thalamic regions. During anesthesia with ketamine, acetylcholine turnover rates were reduced in the caudate nucleus and the hippocampus, but not in the cerebral cortex and the hypothalamic and thalamic regions. The results suggest that acetylcholine turnover rate and utilization are related to anesthetic induced electrophysiologic changes in cortical and subcortical structures.

Disposition of propranolol isomers in mice.

l-Propranolol was found to protect mice from hyperbaric oxygen-induced seizures. The disposition of effective doses of propranolol isomers in mice was followed using stereospecific antibodies with a radioimmunoassay procedure. Serum and tissue concentrations were determined and correlated with the protective effect. Following racemic administration, there were no differences in serum disposition of d- and l-propranolol, although there was initially a preferential uptake of the 1-isomer both into cardiac and brain tissue. The d-isomer exerted synergistic action on the 1-isomer protective effect.