Page 124 - Haematologica March 2020

L. de Swart et al.
definition implies that patients regularly receiving fewer than 3 units per 16 weeks are defined as RBCT-indepen- dent, but these patients might also be subject to the dele- terious association with RBCT. In addition, patients may respond to therapeutic interventions, such as ESA, lenalidomide or iron chelators and become RBCT-inde- pendent again. The conclusion was that the severity of anemia was the leading cause of impaired survival rather than RBCT dependency.24 However, the definition of severe anemia (<9 g/dL in males and <8 g/dL in females) implies that the majority of these patients were regularly transfused, as confirmed in the study.24 This study also showed that the transfusion rate was significantly associ- ated with an increased risk of cardiac complications. The risk of cardiac complications was significantly higher in patients with a RBCT intensity of >3 units per month compared to that in patients transfused with <1 unit per month.24 In an open forum discussion RBCT dependency was even defined much higher, at 2 units per month in a 3-month interval.25 In a Spanish study of 191 transfused patients with MDS, the interval between each transfusion was used to calculate the transfusion intensity.26 It was concluded that high transfusion intensity was associated with decreased survival and increased risk of development of acute myeloid leukemia, in concordance with our study. Interestingly, the cumulative transfusion burden was not a prognostic factor when the transfusion intensity was included in the model.26
The traditional evaluations of the prognostic impact of factors influencing outcome have used standard time-to- event methods based on variables at diagnosis; however, many variables in MDS may change over time. This aspect can be addressed by using proportional hazards regression with time-varying covariates. The EUMDS Registry is collecting its observational data at registration of each new patient (within 100 days after diagnosis) and follow-up data at 6-monthly intervals. This practice leads to regular visit intervals of 6 months. For many patients in this dataset, the value of the recorded transfusion rate var- ied strongly over time, as shown in the Online Supplementary Files. We therefore calculated the RBCT rate at each reported visit during all preceding visit intervals between the date of the first RBCT and the date of the last visit, leading to a “smoothed” variable, defined as dose density. This reflects an average rate of receiving transfu- sions during the whole observation period with transfu- sions. The relatively low number of red cell units trans- fused per month can be explained by the remarkable vari- ation of the transfusion rate over time, even when using interval visit reports of 6 months’ duration.
Baseline age, bone marrow percentage category, num- ber of cytopenias, and the EQ-5D Index retained their sig- nificant prognostic impact in the proportional hazards regression with time-varying explanatory variables. The non-linear component of the dose density effect was also retained (P<1x10-4). The unfavorable effect of the dose density increased until a dose density of about 2 units per month and leveled off thereafter. A similar form and effect was observed when using the cumulative dose of RBCT units over time in an identical multivariate regression model with the same variables (data not shown). The nega- tive impact of the cumulative RBCT dose started already at the time of administering the first RBCT and did not increase any further beyond 30 units received (data not shown).
Many patients showed a (temporary) decrease of the RBCT dose density, reflecting response to ESA,27 lenalido- mide,28 and/or iron chelators12 in 22%, 53% and 40% of the treated patients, respectively. The observed patterns of dose density trajectories suggest that receipt of ESA, lenalidomide and/or iron chelation modulates the dose density and we therefore included these variables as con- founding variables in the regression model. This analysis showed that the impact of the dose density remained sim- ilar to that in the previous analyses, but in contrast to the previous analyses there is some evidence that the dose density effect continued to increase beyond 2 units per month after correction for the three interventions.
Red blood cells are usually transfused after a certain period of storage, but the survival of stored red blood cells depends on this period.29,30 Transfusion of stored red cells leads to pro-inflammatory reactions, associated with a higher risk of infection and increased levels of circulating iron and, in particular, NTBI species, which enhance bac- terial growth in vitro.31,32 Infusion of autologous red blood cells from healthy volunteers after prolonging storage up to 6 weeks resulted in increased extravascular hemolysis, decreased red cell survival, elevated NTBI and ferritin lev- els in units transfused after 6 weeks compared to units transfused after shorter shortage.33 Excess toxic iron species, including NTBI and especially its component LPI,34 catalyze the cellular generation of reactive oxygen species. Oxidative stress may lead to pro-inflammatory responses and to oxidation of lipids, proteins and DNA causing cell and tissue damage.35,36 Elevated NTBI levels after a single unit of RBC stored for 6 weeks normalize within 24 hours.37 However, in multi-transfused patients (cumulative number of units ≥10) with MDS, NTBI and LPI remained elevated until the next transfusion.17
In conclusion, the negative association of transfusions on PFS already occurs at low RBCT dose densities below 3 units per 16 weeks. This indicates that the RBCT dependency in patients transfused at relatively low rates, who are usually considered as untransfused patients, may be considered as an indicator of poor prognosis for PFS. This poor prognosis in transfusion-dependent patients might be the result of direct toxicity of iron radicals result- ing from the RBCT or the result of concomitant disease progression, including hematopoietic impairment. Data from our group provide support for the direct toxicity of RBCT density on outcome, because patients had a better outcome if treated with chelators, which remove toxic iron radicals effectively. Future studies, including interven- tional studies, are needed to confirm our observations, which may lead to adaptions of the current recommenda- tions.
Acknowledgments
The authors and members of the steering committee of the EUMDS Registry would like to thank all local investigators and operational team members for their contribution.
Funding
The work of the EUMDS Registry is supported by an educa- tional grant from Novartis Pharmacy B.V. Oncology Europe, and Amgen Limited. This work is part of the MDS-RIGHT activities, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement n. 634789 - “Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time”.
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haematologica | 2020; 105(3)