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Immunosuppressive therapy in myelodysplastic syndromes
continued from the previous page
Deeg, HJ et al.
Scott BL et al.
2004 ATG40mg/kg/dforfourdoses 14
+ etanercept 25 mg s.c. twice a week for 8 weeks. If no hematologic
by week 8, etanercept three times per week for additional 8 weeks.
2010 ATG 40 mg/kg/d for 4 doses + 25
etanercept 25 mg s.c. twice a week for 2 weeks, every month
for 4 months
Low: 7% Intermediate-1: 71% Intermediate-2: 21%
Low: 44%
Intermediate-1: 56%
RA: 64% RARS: 7% RAEB-I: 7% RAEB-II: 21%
RA: 16%
RARS: 8% RCMD: 72% RAEB-I: 4%
CR: 15% HI-E: 39% TI: 39%
CR: 4%
HI-E: 62%
Not reported (31)
Not reported (38)
AE: adverse events; ATG: anti-thymocyte globulin; h-ATG: horse anti-thymocyte globulin, r-ATG: rabbit anti-thymocyte globulin, AZA: azacitidine, CMML: chronic myelomonocytic leukemia; CR: complete remission; CTCAE: Common Terminology Criteria for Adverse Events; HI-E: hematologic improvement-erythroid; IPSS: International Prognostic Scoring System; MDS-U: unclassifiable myelodysplastic syndrome; PR: partial remission; RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB: refractory anemia with excess blasts; RCMD: Refractory cytopenia with multilineage dysplasia; TI: transfusion independence.
Methods
Date sources and search strategy
This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines.24 MEDLINE via PubMed, Ovid EMBASE, the COHRANE registry of clinical trials (CENTRAL), and the Web of Science electronic databases were searched without language restriction from inception through September 2018, using the following combination of free-text terms linked by Boolean operators: (“MDS” OR “myelodysplasia” OR “myelodysplastic syndrome”) AND (“IST” OR “immunosup- pressive therapy” OR “immunosuppression” OR “ATG” OR “anti- thymocyte globulin” OR “tacrolimus” OR “cyclosporine” OR “sirolimus” OR “prednisone” OR “prednisolone” OR “steroids” OR “etanercept” OR “alemtuzumbab”).
We performed a gray literature search through: 1) manual search of bibliographies of all identified studies; and 2) conference proceedings and abstracts of the following annual meetings: American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, and European Society of Medical Oncology.
Study selection and endpoints
Two reviewers (MS and JPB) independently screened the titles and abstracts of all retrieved studies for eligibility and removed duplicates. Subsequently, full texts of the potentially eligible stud- ies were reviewed for eligibility. We excluded studies that: 1) lack information on either ORR or CR rate; 2) review articles, editori- als, and correspondence letters that did not report independent data; 3) case series and studies reporting outcomes on fewer than five patients; and 4) retrospective studies. There was no disagree- ment among the two reviewers regarding the inclusion of any study. The study selection process is illustrated in a flow diagram (Figure 1).
Prospective cohort studies or clinical trials investigating the use of IST for the treatment of MDS were included. IST was defined as receipt of one or a combination of the following drugs: rabbit and horse ATG, CsA, sirolimus, mycophenolate mofetil and mon- oclonal antibodies (etanercept, alemtuzumab).
The primary outcomes were ORR and CR rate. Secondary out- comes included rates of HI-E, TI, and AML progression. ORR was defined based on the 2006 modified International Working Group (IWG) response criteria for MDS.25
Data extraction
Two investigators (MS and JPB) extracted data using a standard- ized data-extraction form, and a third investigator (SG) performed a cross-check for data accuracy. A more detailed description of the extracted information is provided in the Online Supplementary Methods.
Quality assessment
The quality of each study was assessed by two authors (MS and JPB) using the modified Down and Black checklist.26 Quality assessments for individual studies are provided in Online Supplementary Table S1.
Statistical analysis
Random-effects models were used to pool ORR, rates of CR, HI-E, TI, and progression to AML. All effect sizes underwent log- arithmic transformation prior to pooling using an inverse variance weighting approach. Heterogeneity of studies was determined using Cochran Q and I2 indices and significant heterogeneity (defined as I2 > 60%) was further explored with sensitivity analy- ses.27 Subgroup analyses were planned based on the type of IST used. All analyses were performed with Comprehensive Meta- Analysis (CMA 2.2, Biostat).
Results
Description of included studies
The flow diagram of study selection based on the MOOSE guidelines is shown in Figure 1. An electronic search of PubMed, EMBASE, the Cochrane Library, and the Web of Science plus a manual search retrieved a total of 258 publications after removal of duplicates. Of the 258 articles reviewed, 156 articles were excluded on the basis of the title and abstract review if the article was clearly labeled as a review article, editorial, correspondence letter, case series or retrospective study in the title or abstract. A total of 102 articles were reviewed in full text. Of these, 80 articles were excluded because they were reviews, basic science articles, presented insufficient data (<5 patients), only showed pre- liminary results, or were retrospective in nature. Of the 22 studies included, there were 9 prospective cohort stud- ies13,21,28-32 and 13 clinical trials.16-20,33-40 Patients were treated with ATG , ATG + CsA , ATG + Etanercept (Table 1), CsA (Table 2), and other IST regimens (Table 3).
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