All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combinationbased therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% ؎ 3.4% and 91.7% ؎ 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n ؍ 80) were 94.8% ؎ 2.5% and 97.4% ؎ 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RAR␣ types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.combination therapy ͉ 5-year EFS ͉ 5-year OS ͉ residual disease ͉ arsenic retention A cute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemia (AML) and is characterized by an accumulation of abnormal promyelocytes in the bone marrow and a severe bleeding tendency. Additionally, in the great majority of cases, APL is associated with the t(15,17) chromosomal translocation and resultant PML-RAR␣ transcripts that encode the leukemogenic PML-RAR␣ fusion protein (1). Five decades ago, APL was the most fatal type of acute leukemia and was considered essentially untreatable (2). The first breakthrough came with the use of anthracyclines, which improved the complete remission (CR) rate but provided a low 5-year overall survival (OS) (3). The introduction of all-trans retinoic acid (ATRA) therapy resulted in terminal differentiation of APL cells and a 90-95% CR rate in patients (1, 4), and subsequent combination of ATRA with chemotherapy raised the 5-year disease-free survival (DFS) rate up to 74% (5). In the 1990s, significant benefits of arsenic trioxide (ATO) were reported, which further improved the outcome of patients with APL (6, 7). ATO exerts dose-dependent dual effects on APL cells, with low concentrations inducing partial differentiation and relatively high concentrations triggering apoptosis. Of note, both ATRA and ATO induce catabolism of the PML-RAR␣ fusion protein, demonstrating a paradigm for rationally targeted therapy in leukemia. However, between 20% and 30% of newly diagnosed APL patients treated with regimens based on the use of ATRA or ATO as single agents will develop disease recurrence or drug resistance.To improve further the clinical outcome of APL, therapeutic strategies should be designed to include combinatorial use of drugs with distinct but convergent mechanisms that may amplify treatment effic...
Twenty cases of patients with relapsed acute promyelocytic leukemia (APL) were entered into this study for evaluating the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide (As 2 O 3 ). As 2 O 3 was given at a daily dose of 0.08 mg/kg intravenously for 28 days. Pharmacokinetic study was carried out in eight patients. 16/20 (80%) patients achieved CR. The occurrence of some toxic events including gastrointestinal disturbance, facial edema and cardiac toxicity seemed reduced in the low-dose group than those in the standard-dose group. Differentiation changes were observed in peripheral blood, as well as in bone marrow (BM). Pharmacokinetic study showed that the plasma concentration increased soon after administration of As 2 O 3 with the peak values of 1.535-3.424 mol/l. After infusion, the plasma concentration was around 0.1-0.5 mol/l. The arsenic concentration of the plasma of BM aspirates 24 h after administration in five patients was close to the level needed for differentiation-inducing effect. The estimated 2-year OS and RFS were 61.55 ± 15.79% and 49.11 ± 15.09% respectively, with no difference as compared with those in patients treated with conventional dose (P = 0.2865 and 0.7146, respectively). In conclusion, we demonstrated that low-dose As 2 O 3 had the same effect as the conventional dosage and the mechanism of low-dose arsenic seemed to primarily induce differentiation of APL cells. Leukemia (2001) 15, 735-741.
SUMMARYIn this paper, the decentralized adaptive neural network (NN) output-feedback stabilization problem is investigated for a class of large-scale stochastic nonlinear strict-feedback systems, which interact through their outputs. The nonlinear interconnections are assumed to be bounded by some unknown nonlinear functions of the system outputs. In each subsystem, only a NN is employed to compensate for all unknown upper bounding functions, which depend on its own output. Therefore, the controller design for each subsystem only need its own information and is more simplified than the existing results. It is shown that, based on the backstepping method and the technique of nonlinear observer design, the whole closed-loop system can be proved to be stable in probability by constructing an overall state-quartic and parameterquadratic Lyapunov function. The simulation results demonstrate the effectiveness of the proposed control scheme.
AML1-ETO fusion gene is generated from chromosomal translocation t(8;21) mainly in acute myeloid leukemia M2 subtype (AML-M2). Its spliced variant transcript, AML1-ETO9a, rapidly induces leukemia in murine model. To evaluate its clinical significance, AML1-ETO9a expression was assessed in 118 patients with t(8;21) AML-M2, using qualitative and nested quantitative reverse transcriptase (RT)-PCR methods. These cases were accordingly divided into the AML1-ETO9a-H group (n ¼ 86, positive for qualitative RT-PCR, with higher level of AML1-ETO9a by quantitative RT-PCR) and the AML1-ETO9a-L group (n ¼ 32, negative for qualitative RT-PCR, with lower but still detectable level of AML1-ETO9a by quantitative RT-PCR). C-KIT expression was significantly increased in the AML1-ETO9a-H group, as compared with the AML1-ETO9a-L group. Of the 36 patients harboring C-KIT mutations, 32 patients overexpressed AML1-ETO9a (P ¼ 0.0209). Clinically, AML1-ETO9a-H patients exhibited significantly elevated white blood cells count, less bone marrow aberrant myelocytes, increased CD56 but decreased CD19 expression (P ¼ 0.0451, P ¼ 0.0479, P ¼ 0.0149 and P ¼ 0.0298, respectively). Moreover, AML1-ETO9a overexpression was related to short event-free and overall survival time (P ¼ 0.0072 and P ¼ 0.0076, respectively). Taken together, these data suggest that AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) AML-M2.
SummaryEltrombopag, a thrombopoietin receptor agonist, raises platelet counts and reduces bleeding in patients with immune thrombocytopenia (ITP). In Chinese patients, eltrombopag was evaluated at an initial dose of 25 mg, vs. 50 mg for non-Asians, because the plasma exposure of eltrombopag is higher in East Asians. A multicentre, double-blind, randomised, placebocontrolled, 8-week, phase III study enrolled 155 patients with chronic, previously treated ITP. Dosage could be adjusted (25-75 mg/day) to maintain platelet counts 50-250 9 10 9 /l. The primary efficacy endpoint was the proportion of patients with a platelet count ≥50 9 10 9 /l after Day 42. Pharmacokinetics and pharmacodynamics of eltrombopag were analysed in an open-label extension. After Day 42, 57Á7% of eltrombopag-treated and 6Á0% of placebo-treated patients achieved platelet counts ≥50 9 10 9 /l.Odds of achieving a platelet count ≥50 9 10 9 /l were 26Á08 times greater with eltrombopag than placebo (P < 0Á001). Compared with placebo, time to response and duration of response were better with eltrombopag (P < 0Á001) and the odds of any bleeding were reduced by 72% (P = 0Á001). Tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics were similar to previous findings in East Asian patients. In conclusion, in Chinese patients with chronic ITP, eltrombopag 25 mg once daily, elevated platelet counts to a safe range and reduced bleeding.
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