Use of immunosuppressive therapy for management of myelodysplastic syndromes: a systematic review and meta-analysis

Abstract

Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different immunosuppressive regimens, the lack of high-quality studies, and the absence of validated predictive biomarkers pose important challenges. We conducted a systematic review and meta-analysis according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and searched MEDLINE via PubMed, Ovid EMBASE, COCHRANE registry of clinical trials (CENTRAL), and the Web of Science without language restriction from inception through September 2018, as well as relevant conference proceedings and abstracts, for prospective cohort studies or clinical trials investigating IST in MDS. Fixed and Random-effects models were used to pool response rates. We identified nine prospective cohort studies and 13 clinical trials with a total of 570 patients. Overall response rate was 42.5% [95% confidence interval (CI): 36.1-49.2%] including a complete remission rate of 12.5% (95%CI: 9.3-16.6%) and red blood cell transfusion independence rate of 33.4% (95% CI: 25.1-42.9%). The most commonly used forms of IST were anti-thymocyte globulin alone or in combination with cyclosporin A with a trend towards higher response rates with combination therapy. Progression rate to acute myeloid leukemia was 8.6% per patient year (95%CI: 3.3-13.9%). Overall survival and adverse events were only inconsistently reported. We were unable to validate any biomarkers predictive of a therapeutic response to IST. IST for treatment of lower-risk MDS patients can be successful to alleviate transfusion burden and associated sequelae.

Figure 1.

Flow chart showing study selection as per the MOOSE guidelines. The search strategy and stepwise process of study selection used in this meta-analysis. MEDLINE via PubMed, Ovid EMBASE, the COHRANE registry of clinical trials (CENTRAL), and the Web of Science electronic databases were searched with no 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 “immunosuppressive 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”). Two authors (MS and JPB) independently screened the titles and abstracts of all retrieved studies for eligibility and removed any duplicate records. In a second step, full texts of the potentially eligible studies were reviewed for the final eligibility. Review, basic science articles and articles with insufficient patient number (< 5 patients) as well as preliminary studies and retrospective studies were excluded.

Figure 2.

Overall and complete response rates to various forms of immunosuppressive therapy (IST). Forest plots of odds ratios (squares, proportional to study weights used in meta-analysis, 95% confidence intervals) for various forms of IST with the summary measures (center line of diamond) and associated confidence intervals (lateral tips of diamond) for overall response rate (ORR) and complete response (CR) rate are shown in panel (A) and (B), respectively.

Figure 3.

Rate of hematologic improvement in the erythroid lineage (HI-E) and red blood cell transfusion independence. Forest plots of odds ratios (squares, proportional to study weights used in meta-analysis, 95% confidence intervals) for various forms of immunosuppressive therapy (IST), with the summary measure (center line of diamond) and associated confidence intervals (lateral tips of diamond) for hematologic improvement in the erythroid lineage (HI-E) and achievement of red blood cell transfusion independence (TI) are shown in panel (A) and (B), respectively.

Figure 4.

Rate of acute myeloid leukemia (AML) progression during study duration. Forest plots of odds ratios (squares, proportional to study weights used in meta-analysis, 95% confidence intervals) for various forms of immunosuppressive therapy (IST), with the summary measure (center line of diamond) and associated confidence intervals (lateral tips of diamond) for rate of transformation to AML during the study period.