| Objective:Treatments for myelodysplastic syndrome(MDS)based on prognostic risk and clinical medical practice included different mechanism agents such as hypomethylation agent(HMA),chemotherapy,targeting treatment and immunomodulating agents,single or combined with HMA,allogeneic hematopoietic stem cell transplantation(Allo-HSCT)and best support care(BSC).HMA included azacitidine(AZA),decitabine(DAC).However,currently clinical trials to compare the efficacy and safety of these regimens were not enough and showed different conclusions.Our study evaluated and compared the overall survival rate(OS),efficacy and safety of demethylation regimens and other regimens for MDS patients by network meta-analysis,with a view to comprehensive clinical treatment and individualized treatment of adult MDS patients,providing evidence-based medical evidence,prolonging survival time and improving life quality.Methods: Computer searched Pub Med,EMBASE,CNKI,CBM,VIP,and Wan Fang Data databases,and collected randomized controlled studies,case-control studies and cohort studies of demethylation regiments and other regiments and adult MDS.Extract the survival data,efficacy and adverse events data of patients with MDS.The data included the first author,publication year,research location,research type,source of research subjects,age distribution,basic information of the experimental group and control group,follow-up time and observation endpoints,evaluation indicators,IPSS scores and other clinical baseline characteristics.The Cochrane bias risk assessment tool and the Newcastle-Ottawa scale were used to evaluate the quality of the included original studies,and the Bayesian Markov Chain Monte Carlo(MCMC)random effects model was used to calculate the treatment measures.efficacy and safety OR(HR)value and 95% CI,were used to compare the advantages and disadvantages of ten treatment options.For survival data(OS),the NMA adopting survival endpoints combines binary counts and hazard ratio statistics in an integrated analysis on the hazard ratio scale,which is achieved in a single analysis by estimating the cumulative risk of each test group that reports count data.Combination of count and hazard ratio data was used to compare the effects of ten treatment options on overall survival.Results:1.Clinical baseline characteristics: 5436 Chinese and English literatures were retrieved,with a total of 4071 MDS patients.The publication period is from 2002 to 2020.There are 10 kinds of comprehensive therapies involving Allo-HSCT,AZA,AZA+LEN,AZA+pracinostat,AZA+vorinostat,BSC,CHG,DAC,IA+DAC,LEN and the combination of different treatments.Among the studies included in the Meta-analysis,6 studies were rated as low bias studies,and 6 studies were rated as highly biased studies.2.Network meta-analysis of overall survival: 20 studies were included with OS as the end point(totally 2772),including 11 studies with HR and 95%CI as the effect indicator(totally1879),5 studies with binary data as the effect indicator(totally 496),and 4 studies with the median survival time as the effect indicator(totally 397).Taking AZA as the common reference,the results showed that there was no significant difference between Allo-HSCT and AZA except that the treatment of Allo-HSCT was better than that of AZA,BSC and worse than that of AZA;The top three treatments were Allo-HSCT,AZA+vorinostat and AZA.3.Efficacy outcome indicator analysis: 1 Total response rate: 17 studies reported that the ORR,of MDS took AZA as the public reference,and the network meta-analysis showed that CHG treatment regimen ORR was the highest.The curative effect of each therapy is better than that of BSC;DAC and AZA,and the top three schemes of AZA+Vorinostat;are: CHG,DAC and AZA+LEN.(2)17 studies reported MDS’s CRR(totally 2970).Taking AZA as the public reference,the network meta-analysis showed that the CRR of Allo-HSCT treatment regimen was the highest.The curative effect of each treatment was better than that of BSC;except BSC,and the difference was not statistically significant.The top three schemes were Allo-HSCT,CHG and DAC.3Thirteen studies reported MDS’s PR(totally 2231).Network meta-analysis showed that the PR of AZA+LEN treatment regimen was the highest.The curative effect of AZA+LEN,AZA and AZA+Vorinostat is better than that of BSC,and that of AZA+LEN is better than that of DAC,The top three schemes are AZA+LEN,AZA+Vorinostat and CHG.(4)eight studies reported MDS’s m CR(totally 1396).The network meta-analysis showed that the DAC treatment regimen ranked highest in the m CR indicator.The efficacy of DAC therapy was significantly better than that of AZA,AZA+LEN and CHG,and the top three schemes were DAC,AZA+Vorinostat and AZA.5 6 studies reported MDS’s HI(totally1045).The network meta-analysis showed that the AZA+LEN treatment regimen ranked highest in the HI indicator.The efficacy of AZA therapy was significantly better than that of BSC,and the top three schemes were AZA+LEN,AZA and DAC.4.Network meta-analysis of safety outcome indicators:(1)7 studies reported anemia in MDS(totally 1103).Taking AZA as the public reference,the results of NMA showed that the treatment regimen of Len ranked the highest in the indicator of anemia.There was no significant difference among the treatment schemes.(2)12 studies reported neutropenia in MDS(totally 2054).NMA results showed that BSC regimen ranked highest in neutropenia.Neutropenia events produced by AZA were more than those produced by BSC,and the difference was statistically significant.The top three treatments are BSC,CHG and AZA.(3)11 studies reported thrombocytopenia in MDS(totally 1821).NMA results showed that BSC regimen ranked highest in thrombocytopenia;there was no significant difference among treatments;the top three treatments were BSC,CHG and DC.(4)Nine studies reported the gastrointestinal response of MDS(totally 1216).Taking AZA as the public reference,the results of NMA showed that the treatment regimen of AZA ranked the highest in the indicator of gastrointestinal response.There was no significant difference among the treatment schemes.(5)Twelve studies reported MDS infection(totally 1832).The results of NMA showed that the treatment regimen of CHG was the best in the indicator of infection,followed by BSC.There was no significant difference among the treatment schemes.(6)Hemorrhage of MDS was reported in 9 studies(totally 1423).(7)The results of NMA showed that CHG treatment regimen ranked best in bleeding indicator,followed by BSC.There was no significant difference among the treatment schemes.Conclusion: 1.In terms of overall survival rate,HSCT scheme significantly improved the OS of patients compared with AZA,and the effect of HMA and its combination scheme was equivalent to that of single-agent AZA in improving survival.2.As to the effectiveness indicator,the top three schemes in the ORR indicator are: CHG,DAC and AZA+LEN;the CRR indicator is Allo-HSCT,CHG,DAC;the top three schemes in the PR indicator are: AZA+LEN,AZA+Vorinostat and CHG;the top three schemes in m CR indicators are: DAC,AZA+Vorinostat and AZA.The top three schemes in the HI indicator are:AZA+LEN,AZA and DAC.3.In the safety indicators,there is no significant difference between the treatment options in anemia,thrombocytopenia,gastrointestinal reactions,infections,and bleeding.4.For patients with adverse reactions such as ORR and neutropenia,thrombocytopenia,infection,bleeding,etc.,the CHG scheme is the drug with the best balance of efficacy and safety.Combining ORR and reducing anemia,AZA+Pracinostat is the best candidate drug.To integrate ORR and reduce gastrointestinal adverse reactions,the first consideration should be to use AZA+Pracinostat,AZA+LEN drugs. |
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