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Overview of Targeted Therapies for Adult T-Cell Leukemia/Lymphoma.
Nasr, R, Marçais, A, Hermine, O, Bazarbachi, A
Methods in molecular biology (Clifton, N.J.). 2017;:197-216
Abstract
Adult T-Cell Leukemia/lymphoma (ATL) is the first human malignancy associated with a chronic infection by a retrovirus, the human T-cell lymphotropic virus type I (HTLV-I). ATL occurs, after a long latency period, only in about 5% of 10-20 millions infected individuals. ATL has a dismal prognosis with a median survival of less than 1 year, mainly due to its resistance to chemotherapy and to a profound immunosuppression. The viral oncoprotein, Tax, plays a major role in ATL oncogenic transformation by interfering with cell proliferation, cell cycle, apoptosis, and DNA repair. The diversity in ATL clinical features and prognosis led to Shimoyama classification of ATL into four clinical subtypes (acute, lymphoma, chronic, and smoldering) requiring different therapeutic strategies. Clinical trials, mainly conducted in Japan, demonstrated that combination of chemotherapy could induce acceptable response rate in the lymphoma subtype but not in acute ATL. However, long-term prognosis remains poor for both subtypes, due to a high relapse rate. Similarly, whether managed by a watchful waiting or treated with chemotherapy, the indolent forms (smoldering and chronic) have a poor long-term outcome. An international meta-analysis showed improved survival in the leukemic subtypes of ATL (chronic, smoldering as well as a subset of the acute subtype) with the use of two antiviral agents, zidovudine and interferon-alpha, and accordingly, this combination should be considered the standard first-line treatment in this context. ATL patients with lymphoma subtype benefit from induction chemotherapy, given simultaneously or sequentially with an antiviral combination of zidovudine and interferon-alpha. Allogeneic hematopoietic stem cells transplantation remains a promising and potentially curative approach but is limited to a small number of patients. Novel drugs such as arsenic trioxide in combination with interferon-alpha or monoclonal antibodies such as anti-CXCR4 have shown promising results and warrant further investigation.
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2.
Arsenic trioxide combined with transarterial chemoembolization for primary liver cancer: A meta-analysis.
Lv, XH, Wang, CH, Xie, Y
Journal of gastroenterology and hepatology. 2017;(9):1540-1547
Abstract
BACKGROUND AND AIM The benefit of combination therapy of arsenic trioxide (As2 O3 ) and transarterial chemoembolization (TACE) is debated. This meta-analysis was conducted to determine whether As2 O3 &TACE therapy achieves better therapeutic effects compared with TACE alone for primary liver cancer. METHODS A systematic search of both English and Chinese databases was conducted for randomized controlled trials. The main outcomes were therapeutic responses, survival rates, improvement in quality of life, and adverse events. All data analyses in this study were carried out using Review Manager software and STATA software. RESULTS Eighteen randomized controlled trials involving 1412 participants were included. The pooled objective response rate was significantly higher in the As2 O3 &TACE group compared with the TACE group (relative risk [RR] 1.36, 95% confidence interval [CI] 1.16-1.58, P < 0.0001), and the pooled clinical benefit rate was also significantly higher (RR 1.18, 95% CI 1.08-1.29, P = 0.0002). A higher pooled result was obtained from the combination group for 1-year survival rate (RR 1.37, 95% CI 1.23-1.53, P < 0.00001). As2 O3 &TACE therapy was not superior to TACE alone for improvement in quality of life (RR 1.15, 95% CI 0.98-1.36, P = 0.09). There was no significant difference in the risk of adverse effects. When a subgroup analysis was performed, both administration methods of As2 O3 (intravenous or arterial) were effective for all evaluating indicators except the improvement in quality of life. CONCLUSIONS Adjuvant As2 O3 therapy combined with TACE achieves better therapeutic effects compared with TACE alone. Both the intravenous administration of As2 O3 and the arterial administration of As2 O3 were good options for clinical practice.
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3.
All-Trans Retinoic Acid plus Arsenic Trioxide versus All-Trans Retinoic Acid plus Chemotherapy for Newly Diagnosed Acute Promyelocytic Leukemia: A Meta-Analysis.
Ma, Y, Liu, L, Jin, J, Lou, Y
PloS one. 2016;(7):e0158760
Abstract
BACKGROUND Recently, the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL), but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL. METHODS We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity. RESULTS Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22-0.67, p = 0.009), overall survival (HR = 0.44, 95% CI: 0.24-0.82, p = 0.009), complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01-1.10; p = 0.03). There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22-1.05; p = 0.07). CONCLUSION Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients.
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4.
[Arsenic trioxide in combination with all-trans retinoic acid for acute promyelocytic leukemia: a systematic review and meta-analysis].
Xu, SN, Chen, JP, Liu, JP, Xia, Y
Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine. 2009;(11):1024-34
Abstract
BACKGROUND The studies have demonstrated that arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) takes effects in treatment of acute promyelocytic leukemia (APL) through different underlying mechanisms. This has established the molecular foundation of ATO plus ATRA therapy. Currently, ATO plus ATRA has also been widely used in clinical practice. OBJECTIVE To assess the efficacy and safety of ATO in combination with ATRA for APL. SEARCH STRATEGY The Cochrane Library (Issue 1, 2009), Cochrane Central Register of Controlled Trials (from 1970 to January 2009), MEDLINE (from 1978 to October 2008), EMBASE (from 1950 to March 2009), Chinese Biological Medical Literature Database (from 1978 to December 2008), CNKI (from 1994 to December 2008), China Medical Academic Conference Database (from 1994 to December 2008) were electronically searched. We also searched the Meta-Register of Controlled Trials, Conference Proceedings of American Society of Hematology (from 1946 to December 2008) and Conference Proceedings of American Society of Clinical Oncology (from 1946 to December 2008) on the internet for grey literature. The authors also hand-searched Chinese periodicals potentially related to the question including Chinese Journal of Hematology, Journal of Experimental Hematology and Journal of Clinical Hematology. INCLUSION CRITERIA All randomized controlled trials comparing ATO plus ATRA with other regimens for the treatment of APL were included. Intervention and comparison regimens include: 1) ATO plus ATRA vs ATO monotherapy; 2) ATO plus ATRA vs ATRA monotherapy; 3) ATO plus ATRA vs ATRA plus chemotherapy; 4) ATO plus ATRA vs ATO+ATRA+chemotherapy. DATA EXTRACTION AND ANALYSIS Related data concerning complete remission rate, overall survival rate, and disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions were extracted independently by two reviewers. The different statistical methods were applied according to different data type with RevMan 5.0 software. RESULTS After merging of the included trials, seven eligible randomized controlled trials with 392 cases were analyzed, among which 6 RCTs were methodologically graded as middle and one as of high risk of bias. The control therapies included ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA. Compared with ATO monotherapy, ATO plus ATRA could improve time to complete remission and relapse rate of newly diagnosed APL, but could not improve the complete remission rate, disease free survival rate, mortality and liver dysfunction of relapsed APL patients based on meta-analysis and sensitivity analysis. Compared with ATRA monotherapy, ATO plus ATRA shortened the time to complete remission, improved the disease free survival rate and relapse rate, but increased the incidence of edema during the treatment. Compared with chemotherapy with ATO plus ATRA, ATO plus ATRA could improve the complete remission rate, relapse rate, mortality and adverse reactions. CONCLUSION For newly diagnosed APL, ATO plus ATRA is superior to ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA, but due to the lack of data about comparison with the current standard treatment regimen (ATRA plus chemotherapy), it is not enough to recommend ATO plus ATRA as a frontline therapy. For relapsed APL, ATO plus ATRA is not superior to ATO monotherapy, and ATRA plus ATO is not a supportive therapy. Due to limitation of sample size and risk of bias from the included trials, the effects of ATO plus ATRA need to be confirmed by large and high-quality randomized controlled trials.
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5.
[Efficacy of arsenic trioxide for acute promyelocytic leukemia: a systematic review and meta-analysis].
Xu, SN, Chen, JP, Liu, JP, Xia, Y
Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine. 2009;(9):801-8
Abstract
OBJECTIVE To systematically review the efficacy and safety of arsenic trioxide (ATO) in treatment of acute promyelocytic leukemia (APL). METHODS The Cochrane Library (Issue 1, 2009), Cochrane Central Register of Controlled Trials (from 1970 to January 2009), MEDLINE (from 1978 to October 2008), EMBASE (from 1950 to March 2009), Chinese Biological Medical Literature Database (from 1978 to December 2008), China National Knowledge Infrastructure (CNKI, from 1994 to December 2008), and China Medical Academic Conference Database (from 1994 to December 2008) were electronically searched. We also searched the Meta-Register of controlled trials, Conference Proceedings of American Society of Hematology (from 1946 to December 2008) and Conference Proceedings of American Society of Clinical Oncology (from 1946 to December 2008) on the internet for grey literature. The related journals in the library of Third Military Medical University were hand-searched. The randomized controlled trials (RCTs) of ATO in treatment of APL were included. We adopted complete remission, overall survival rate, disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions as outcome indicators. Data were entered and analyzed with the Cochrane review manager software 5.0 (RevMan 5.0). RESULTS After merger of the included trials, five eligible RCTs with 328 cases were included. All the RCTs focused on the comparison of all-trans retinoic acid (ATRA) plus ATO regimen with ATRA monotherapy. Meta-analysis showed that the effect indexes for time to complete remission, two-year disease free survival rate, relapse rate, incidence of edema and incidence rate of QT interval prolongation were -1.20 [-1.68, -0.72], 8.64 [1.66,45.00], 0.21 [0.09,0.47], 4.16 [1.46,11.79] and 22.10 [2.75,177.49], respectively. The influences on other outcome indicators such as complete remission and leukocytosis were statistically non-significant. CONCLUSION ATO can prolong disease free survival and reduce the time to complete remission and relapse rate of newly diagnosed APL patients, and increase the incidence of edema and prolongation of corrected QT interval during the treatment. Due to limitation of the included trials, this conclusion needs to be validated by further studies.