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M. Stahl et al.
list that are only applicable to multi-arm studies, 12 out of 22 studies scored at least 15 out of the remaining 20 points. A notable exception in terms of methodological quality was the phase III trial by Passweg et al. comparing ATG + CsA to best supportive care.18 Importantly, treat- ment with ATG + CsA resulted in a hematologic response in 31% of patients in this trial which is comparable to the 33.7% for ATG + CsA in our meta-analysis. Although the limitations in terms of study quality must be kept in mind, the overall comparable results among different studies suggest that our meta-analysis provides robust evidence on the effect of IST in the treatment of MDS.
Previous studies have suggested that IST may contribute to the risk of progression to AML because of a suppression of immune surveillance. However, this seems to be more relevant in high-risk MDS subtypes rather than the lower risk MDS forms that constitute the patients primarily treated with IST.48,49 In our meta-analysis, we found a rate of progression to AML of 8.6% per patient year (95%CI: 3.3-13.9%). The risk of progression to AML varies sub- stantially based on the IPSS risk category as well as the presence of certain cytogenetic abnormalities.50 The majority of patients in our meta-analysis had either low (32.8%) or intermediate-1 (49.2%) risk disease by IPSS (Tables 1-3). In previous studies, the time of progression to AML in the absence of treatment for 25% of patients with IPSS-low and intermediate-1 MDS patients was reported at 10.8 and 3.2 years, respectively.51 Although comparison of our data with these historical results is limited, our meta-analysis does not show a significantly higher AML transformation rate than expected for IPSS lower and intermediate-1 risk MDS patients in general.
Our study has several limitations. In many of these studies, the patients included were selected and judged by the investigators to potentially benefit from IST. Therefore, the efficacy results might be inflated and not necessarily apply to all lower-risk MDS patients. In addi- tion to the heterogeneity of studies and the overall low methodological quality, there were insufficient data to assess adverse events in our meta-analysis. While at least a minimum amount of information on treatment-associat- ed adverse events was provided in 17 out of 22 studies, only 5 studies provided CTCAE grading of adverse events and reported those on a patient level.18,35,39-41 Given the het- erogeneity of adverse event reporting, we were unable to conduct a meta-analysis on the side effect profile of IST in MDS. As IST is most commonly used for lower-risk MDS
patients to alleviate symptom burden resulting from red blood cell transfusion dependence and to limit the detri- mental sequelae of resulting iron overload rather than modifying AML transformation risk, information on treat- ment-associated adverse events is essential for physicians to appropriately counsel patients. We were not able to analyze the effect of IST on platelet transfusion independ- ence as it was reported in only the minority of studies. Lastly, publication bias could not be assessed in this meta- analysis because of the lack of a comparative treatment arm in the majority of the studies.
Given that the median overall survival rate among untreated patients with lower-risk MDS is 5.3 years, a long duration of follow up would be required to detect any survival benefit from IST and data on overall survival were provided in 5 out of 23 studies only. Therefore, we were unable to assess whether IST provides an actual sur- vival benefit in MDS.
Conclusions
In summary, our data showed an ORR of 42.5% and a TI rate of 33.4% for IST in MDS, with ATG-based treat- ment regimens being the most commonly used option. Response rates tended to be higher for combination ther- apy of ATG in conjunction with mostly CsA compared to ATG monotherapy. While we were unable to assess the utility of various biomarkers in predicting response to IST, current guidelines recommend considering IST for symp- tomatic treatment of lower-risk MDS patients to alleviate transfusion burden and associated sequelae. However, given the lack of prospective, randomized, controlled studies, it is difficult to definitively determine the impact of IST on response and survival in patients with MDS, and randomized trials of IST are warranted to confirm our results.
Funding
Amer Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a National Cancer Institute (NCI) Cancer Clinical Investigator Team Leadership Award (CCITLA). Research reported in this publication was supported by the NCI of the National Institutes of Health under Award Number P30 CA016359. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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