-
1.
Tamibarotene maintenance improved relapse-free survival of acute promyelocytic leukemia: a final result of prospective, randomized, JALSG-APL204 study.
Takeshita, A, Asou, N, Atsuta, Y, Sakura, T, Ueda, Y, Sawa, M, Dobashi, N, Taniguchi, Y, Suzuki, R, Nakagawa, M, et al
Leukemia. 2019;(2):358-370
Abstract
Between April 2004 and December 2010, we conducted a prospective randomized controlled study comparing tamibarotene with all-trans retinoic acid (ATRA) in the maintenance therapy of newly diagnosed acute promyelocytic leukemia (APL), and here report the final results of this study with a median follow-up of 7.3 years. Of 344 eligible patients who had received ATRA and chemotherapy, 319 (93%) achieved complete remission (CR). After completion of three courses of consolidation chemotherapy, 269 patients in molecular remission underwent maintenance randomization, 135 to ATRA (45 mg/m2 daily), and 134 to tamibarotene (6 mg/m2 daily) for 14 days every 3 months for 2 years. The primary endpoint was relapse-free survival (RFS). The 7-year RFS was 84% in the ATRA arm and 93% in the tamibarotene arm (p = 0.027, HR = 0.44, 95% CI, 0.21 to 0.93). The difference was prominent in high-risk patients with initial leukocytes ≥ 10.0 × 109/L (62% vs. 89%; p = 0.034). Tamibarotene was significantly superior to ATRA by decreasing relapse in high-risk patients. Overall survival after randomization did not differ (96% vs. 97%; p = 0.520). Secondary hematopoietic disorders developed in nine patients, secondary malignancies in 11, and grade 3 or more late cardiac comorbidities in three. These late complications did not differ between the two arms.
-
2.
Deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation: multicenter phase I study (KSGCT1302).
Tachibana, T, Kanda, J, Machida, S, Saito, T, Tanaka, M, Najima, Y, Koyama, S, Miyazaki, T, Yamamoto, E, Takeuchi, M, et al
International journal of hematology. 2018;(5):578-585
Abstract
UNLABELLED The aim of this study was to assess the safety and optimal dose of deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation (HCT). The primary endpoint was the maximum tolerated dose of deferasirox that was determined by the intrapatient dose escalation methods. A total of 16 patients with post-HCT iron overload were enrolled in the study. After excluding one case of early relapse, 15 remained evaluable. Their median age was 42 years (range 22-68). Median time from HCT to deferasirox administration was 9 months (range 6-84). Deferasirox was started at a dose of 5 mg/kg, and the dose was increased to 7.5 and 10 mg/kg every 4 weeks unless there were no grade ≥ 2 of adverse events. Achievement rates of planned medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in 10 mg/kg (9 of 15), respectively. The reasons for discontinuation of the drug were grade 2 of adverse events (n = 4), late relapse (n = 1), and self-cessation (n = 1). None of the patients developed grade ≥ 3 of adverse events or exacerbation of GVHD. Among 11 evaluable cases, mean value of ferritin decreased from 1560 ng/ml pre-treatment to 1285 ng/ml post-treatment. These data suggested that 10 mg/kg of deferasirox may be maximum tolerated dose when given after HCT. Our dose escalating method of deferasirox is useful to identify the optimal dosage of the drug in each patient. TRIAL REGISTRATION UMIN000011251.
-
3.
Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self-Assembly and Transport Behavior.
Prasad, S, Achazi, K, Schade, B, Haag, R, Sharma, SK
Macromolecular bioscience. 2018;(7):e1800019
Abstract
Herein, a new series of non-ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C-10 and C-18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10-5 m and hydrodynamic diameters in the 8-10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet-visible (UV-Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self-assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non-cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1-anilinonaphthalene-8-sulfonic acid (ANS) and curcumin with binding constant of 1.16 × 1055 m-1 and 1.43 × 106 m-1 , respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.
-
4.
One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.
Inati, A, Kahale, M, Sbeiti, N, Cappellini, MD, Taher, AT, Koussa, S, Nasr, TA, Musallam, KM, Abbas, HA, Porter, JB
Pediatric blood & cancer. 2017;(1):188-196
Abstract
BACKGROUND Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. RESULTS Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
-
5.
Efficacy and Safety of Combined Oral Chelation With Deferiprone and Deferasirox in Children With β-Thalassemia Major: An Experience From North India.
Parakh, N, Chandra, J, Sharma, S, Dhingra, B, Jain, R, Mahto, D
Journal of pediatric hematology/oncology. 2017;(3):209-213
Abstract
OBJECTIVE A combination of desferrioxamine with either deferiprone (DFP) or deferasirox (DFX) for patients with β-thalassemia major who do not achieve negative iron balance with monotherapy has been studied widely. However, poor compliance resulting from the need for parentral administration of desferrioxamine and its cost necessicitates combining 2 oral chelators. METHODS A prospective study was conducted in patients with transfusion-dependent β-thalassemia major in a tertiary care center over 2 years. Patients on either DFP or DFX who were not improving on monotherapy over a long period and persistently maintaining serum ferritin >2500 µg/L were enrolled. Efficacy was assessed by serum ferritin levels assessed at 12 months and 2 years. Complete blood counts and liver and kidney function tests were monitored to assess the safety of the combination of drugs. RESULTS In total, 33 patients with a mean age of 12.67 years (7.5 to 17.5 y) and a mean ferritin of 4835.2394±1443.85 µg/L formed the study cohort.In total, 28 patients completed the 1-year study period; and 12 patients completed 2 years. Mean serum ferritin reduction at 1 and 2 years was 34.99%±18.13% (range, -34.36% to 56.17%) and 44.67%±13.78% (range, 22.17% to 62.74%), respectively. The combination therapy was well tolerated. CONCLUSIONS Combined oral chelation with DFP and DFX has better efficacy than either drug used alone. The combination of drugs was well tolerated and no new adverse effects were observed.
-
6.
Synergistic inhibitory effects of deferasirox in combination with decitabine on leukemia cell lines SKM-1, THP-1, and K-562.
Li, N, Chen, Q, Gu, J, Li, S, Zhao, G, Wang, W, Wang, Z, Wang, X
Oncotarget. 2017;(22):36517-36530
Abstract
A multi-center study from the French Myelodysplastic Syndrome (MDS) Group confirmed that iron chelation therapy is an independent prognostic factor that can increase the survival rate of patients who are suffering from transfusion-dependent low-risk MDS. In this study, we aimed to explore this clinical phenomena in vitro, by exploring the synergistic effect of the iron chelator Deferasirox (DFX) and the DNA methyl transferase inhibitor Decitabine (DAC) in the leukemia cell lines SKM-1, THP-1, and K-562. Treatment with both DFX or DAC promoted apoptosis, induced cell cycle arrest, and inhibited proliferation in all three of these cell lines. The combination of DFX and DAC was much greater than the effect of using either drug alone. DFX showed a synergistic effect with DAC on cell apoptosis in all three cell lines and on cell cycle arrest at the G0/G1 phase in K-562 cells. DFX decreased the ROS levels to varying degrees. In contrast, DAC increased ROS levels and an increase in ROS was also noted when the two drugs were used in combination. Treatment of cells with DAC induced re-expression of ABAT, APAF-1, FADD, HJV, and SMPD3, presumably through demethylation. However the combination of DAC and DFX just had strong synergistic effect on the re-expression of HJV.
-
7.
Benzoate- and Salicylate-Tolerant Strains of Escherichia coli K-12 Lose Antibiotic Resistance during Laboratory Evolution.
Creamer, KE, Ditmars, FS, Basting, PJ, Kunka, KS, Hamdallah, IN, Bush, SP, Scott, Z, He, A, Penix, SR, Gonzales, AS, et al
Applied and environmental microbiology. 2017;(2)
-
-
Free full text
-
Abstract
UNLABELLED Escherichia coli K-12 W3110 grows in the presence of membrane-permeant organic acids that can depress cytoplasmic pH and accumulate in the cytoplasm. We conducted experimental evolution by daily diluting cultures in increasing concentrations of benzoic acid (up to 20 mM) buffered at external pH 6.5, a pH at which permeant acids concentrate in the cytoplasm. By 2,000 generations, clones isolated from evolving populations showed increasing tolerance to benzoate but were sensitive to chloramphenicol and tetracycline. Sixteen clones grew to stationary phase in 20 mM benzoate, whereas the ancestral strain W3110 peaked and declined. Similar growth occurred in 10 mM salicylate. Benzoate-evolved strains grew like W3110 in the absence of benzoate, in media buffered at pH 4.8, pH 7.0, or pH 9.0, or in 20 mM acetate or sorbate at pH 6.5. Genomes of 16 strains revealed over 100 mutations, including single-nucleotide polymorphisms (SNPs), large deletions, and insertion knockouts. Most strains acquired deletions in the benzoate-induced multiple antibiotic resistance (Mar) regulon or in associated regulators such as rob and cpxA, as well as the multidrug resistance (MDR) efflux pumps emrA, emrY, and mdtA Strains also lost or downregulated the Gad acid fitness regulon. In 5 mM benzoate or in 2 mM salicylate (2-hydroxybenzoate), most strains showed increased sensitivity to the antibiotics chloramphenicol and tetracycline; some strains were more sensitive than a marA knockout strain. Thus, our benzoate-evolved strains may reveal additional unknown drug resistance components. Benzoate or salicylate selection pressure may cause general loss of MDR genes and regulators. IMPORTANCE Benzoate is a common food preservative, and salicylate is the primary active metabolite of aspirin. In the gut microbiome, genetic adaptation to salicylate may involve loss or downregulation of inducible multidrug resistance systems. This discovery implies that aspirin therapy may modulate the human gut microbiome to favor salicylate tolerance at the expense of drug resistance. Similar aspirin-associated loss of drug resistance might occur in bacterial pathogens found in arterial plaques.
-
8.
Limitations of serum ferritin to predict liver iron concentration responses to deferasirox therapy in patients with transfusion-dependent thalassaemia.
Porter, JB, Elalfy, M, Taher, A, Aydinok, Y, Lee, SH, Sutcharitchan, P, El-Ali, A, Han, J, El-Beshlawy, A
European journal of haematology. 2017;(3):280-288
-
-
Free full text
-
Abstract
BACKGROUND In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration (LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging (MRI) is unavailable. OBJECTIVES AND METHODS This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox. RESULTS Serum ferritin responses (decreases) occurred in 73% of patients, 80% of whom also have decreased LIC. However, 52% of patients without a serum ferritin response did decrease LIC and by >1 mg Fe/g dw (median 3.9) in 77% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was <4000 ng/mL (r = 0.59; P < 0.0001) and not at higher levels (≥4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89% and 70% of cases when serum ferritin was <4000 or ≥4000 ng/mL, respectively. CONCLUSIONS As serum ferritin non-response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone.
-
9.
Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial.
Lin, CY, Liang, SY, Chang, YC, Ting, SY, Kao, CL, Wu, YH, Tsai, GE, Lane, HY
The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. 2017;(5):357-368
Abstract
Objectives Hypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, a d-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients. Methods This study compared add-on sarcosine (2 g/day) plus benzoate (1 g/day) vs. sarcosine (2 g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12. Results Adjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved. Conclusions This finding suggests N-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms.
-
10.
Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST).
Vichinsky, E, El-Beshlawy, A, Al Zoebie, A, Kamdem, A, Koussa, S, Chotsampancharoen, T, Bruederle, A, Gilotti, G, Han, J, Elalfy, M
Pediatric blood & cancer. 2017;(9)
Abstract
BACKGROUND Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. PROCEDURE Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. RESULTS In total, 267 patients (mean age 3.2 years) predominantly with β-thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years' treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1-7.9) and 4.0% (95% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals. CONCLUSIONS Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.