1.
Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia.
Chen, YB, Li, S, Lane, AA, Connolly, C, Del Rio, C, Valles, B, Curtis, M, Ballen, K, Cutler, C, Dey, BR, et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014;(12):2042-8
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.
2.
Genistein inhibits proliferation and functions of hypertrophic scar fibroblasts.
Cao, C, Li, S, Dai, X, Chen, Y, Feng, Z, Zhao, Y, Wu, J
Burns : journal of the International Society for Burn Injuries. 2009;(1):89-97
Abstract
Hypertrophic scarring is abnormal proliferation of dermal fibroblasts and excessive deposition of extracellular matrix. To date, despite many studies, treatments have not been satisfactory. Genistein, a potent, specific inhibitor of tyrosine protein kinases (TPKs), has been proved to inhibit many kinds of tumour and some fibrotic diseases. The purpose of this study was to investigate the effects of genistein on the proliferation and functions of hypertrophic scar fibroblasts (HSFBs) and the mechanism by which genistein inhibits TPK signal transduction. The first effect was observed by methyl-thiazol-diphenyl-tetrazolium assay and the second by [gamma-(32)p] adenosine triphosphate incorporation assay. The results demonstrated that genistein inhibits the proliferation and function of HSFBs and changes the TPK signal transduction pathway, which can provide an experimental basis for treating HS with genistein.