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Transfusion dose density in lower-risk MDS
visit after starting ESA treatment. Online Supplementary Figure S2 gives the individual dose density over time dur- ing ESA treatment of the 151 responding patients. Overall, 100 patients received treatment with lenalidomide: of these, 53 patients had a reduced transfusion density in the first visit after starting lenalidomide treatment; Online Supplementary Figure S3 shows the individual dose density over time during lenalidomide treatment of the 53 responding patients. Within our study group 186 patients received treatment with iron chelators and 75 patients had a response leading to reduced transfusion densities in the first interval after starting of iron chelation treatment (Online Supplementary Figure S4). In contrast to the dose densities over time during ESA and lenalidomide treat- ment, the longer-term dose densities during iron chelation appeared to show a more stable pattern: subjects receiving a certain level of blood transfusion dose density when they first received iron chelation appeared to maintain that level of dose density. The decline of the dose density was less pronounced, but this might be a reflection of the longer transfusion period before starting chelation treat- ment when compared with the other two interventions.
The observed patterns of dose density trajectories sug- gest that receiving ESA, lenalidomide or iron chelation therapy modulates the dose density and we, therefore, included these variables in the regression model. This analysis resulted in an effect for the dose density similar to that of the previous analyses (Figure 3B), with a P-value of <0.0001. Indeed all variables entered in the regression retained statistical significance, except for platelet count (P=0.47) and neutrophil count (P=0.24). However, the dose density effect continued to increase beyond 1 unit per month after correction for the three interventions (ESA, iron chelation and lenalidomide) up until a dose of 6 units per month (Figure 3C).
Some patients received more than one intervention simultaneously, including 25 patients who received chela- tion and lenalidomide and 88 patients who received ESA and chelation. However, no additional impact could be detected over and above the impact of the two individual interventions.
Discussion
This large prospective, observational study confirmed the reported association of transfusion dose density with reduced PFS in patients with lower-risk MDS.20 More sur- prisingly, we showed in this study that this negative asso- ciation already occurred at a low transfusion rate. In addi- tion, we showed that the risk of progression increased both in the low and high transfusion burden groups when compared to the non-transfused patients. We were even able to show that the deleterious effect of transfusions occurred at a very low transfusion burden (<0.75 units per month or <3 units per 16 weeks as defined by the revised IWG criteria), when the patients were subdivided accord- ing to the revised IWG hematological response criteria.19 These patients with a very low transfusion burden are considered as untransfused patients using the revised IWG response criteria.19
The main focus of our study was to analyze the associ- ation of transfusion rate with outcome, assuming that reg- ularly transfused patients may be exposed to the postulat- ed toxicity of RBCT at a lower transfusion burden than
generally accepted. Several studies have addressed this question using various definitions of transfusion rate. The initial publications describing the impact of RBCT on out- come in MDS compared RBCT-dependent patients with RBCT-independent patients, using RBCT dependency as a time-dependent variable.1,21 These studies were based on various definitions of RBCT dependency,22,23 including a study using a rigid criterion, which implied a RBCT rate of at least 1 unit per month during a period of 2 months.24 In this last study, transfusion dependency occurred in a minority of the patients (35% to 44%). The use of this
A
B
C
Figure 3. Influence of dose density on progression-free survival. (A) Dose density effect on progression-free survival (PFS) in an univariate analysis. (B) Dose den- sity effect on PFS in a multivariate regression model unadjusted for the three treatment variables. (C) Dose density effect on PFS in a multivariate regression model adjusted for treatment with either erythropoiesis-stimulating agent, Iron chelation or lenalidomide.
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