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Transfusion dose density in lower-risk MDS
exclusions are provided in the Online Supplementary Data. Table 1 and Online Supplementary Table S1 show the patients’ baseline demographics. For the landmark analy- sis patients were defined as untransfused if they had never received a transfusion from diagnosis until the end of the study period (death or progression), or if they had received transfusion only once (n=751). Patients were defined as transfused if they had received multiple trans- fusions (n=516) within the first year of follow-up (visit 3 = landmark). Regular transfusions were usually initiated during the first 6 months. Using visit 3 as the landmark ensured that the majority of patients who received more than one transfusion were correctly identified.
Distribution of transfusion dose density
The distribution of non-zero dose densities at the third visit (the landmark visit) is shown in Figure 1. Mean dose density among those who had received a transfusion at 1 year of follow-up was 1.24 units per month, with a medi- an of 0.88 units per month (interquartile range, 0.31 – 1.85). Dose densities of the transfused patients declined on approach to the final recorded interval, if the patient died or progressed to higher-risk MDS during the last interval (Online Supplementary Figure S1). This implies that patients received fewer transfusions per month in the interval during which death occurred than in the preced- ing intervals. Presumably, the treatment focus switches to palliative care at home on the approach to death. Patients alive at the last recorded visit and with no signs of pro- gression did not show an increase of transfusion density over time (Online Supplementary Figure S1).
Outcome of patients stratified according
to transfusion status at the landmark 1 year after registration
The patients’ characteristics at the time of the landmark visit 3 stratified according to transfusion status are shown in Online Supplementary Table S2. One hundred forty-five subjects untransfused at visit 3 went on to have transfu- sions after the landmark visit. Out of 516 transfused by the time of the landmark, 288 subjects were not reported to have received any further transfusions, but of these 288, 125 subjects did not have any further visits and another 91 had only one additional visit. Of the 163 sub- jects who had one or more additional visits (91+72, respectively), 73 received treatment with ESA, 19 with lenalidomide, ten with hypomethylating agents, two with hydroxycarbamide, and three with iron chelators. Unadjusted PFS stratified by transfusion status (trans- fused n=516, untransfused n=751) at the third visit is pre- sented in Figure 2A. The overall PFS of the untransfused patients at visit 3 was significantly better (P<0.0001) than that of the transfused patients.
Transfused patients were divided into those receiving above (high density) or below (low density) the median value (0.87 units per month) of non-zero dose densities. Unadjusted PFS stratified by transfusion status and dose density (untransfused n=751, low dose density n=258, high dose density=258) at the third visit is presented in Figure 2B. The overall PFS of the three groups of patients, stratified according to the dose density at visit 3, was sig- nificantly different (P<0.0001). We evaluated the time to progression in the three groups of patients by censoring those who died before progression (Figure 2C). The haz- ard ratios for the patients in the low and high density
groups were 1.85 (95% CI: 1.24-2.76), and 3.79 (95% CI: 2.65-5.42) relative to the non-transfused group. The recently revised International Working Group (IWG) hematologic response criteria for patients with MDS refined RBCT burden by dividing patients into three cat- egories (non-transfused patients, patients with a low transfusion burden (0.75-2 units per month) and those with a high transfusion burden (≥2 units per month).19 We therefore repeated the analysis, subdividing the patients into four groups: no transfusions, >0 to <0.75 (low transfusion burden), 0.75 to 1.75 (mid transfusion burden) and >1.75 (high transfusion burden). The results are shown in Figure 2D. The main effect occurred for low dose densities, such that the outcomes of the mid and high transfusion density groups were similar. The low transfusion burden group of Figure 2D (density >0 - <0.75 units per month) is almost identical to the low bur- den group (density <0.89 units pwer month) of Figure 2B. MDS-related causes of death increased from 28% in the non-transfused group to 39% and 48% in the mid and high transfusion burden groups, respectively (data not shown).
Impact of individual prognostic factors
The univariate effect of various covariates on outcome was investigated in order to discover the appropriate functional form for the covariates (i.e., to discover whether a linear or non-linear form was best) and to dis- cover appropriate ways of adjusting for confounding covariates. Increasing RBCT dose density was associated with inferior PFS (P<1x10-4). The functional form is shown in Figure 3A. The effect of the dose density increased until a dose density of about 1 unit per month; thereafter, the effect was flat. Baseline age (as a continu- ous variable) was strongly associated with PFS (P<1x10-4) in univariate regression analyses, as were baseline MDS diagnosis (P<1x10-4), quality of life measured by the EQ- 5D Index (P<1x10-4), country of origin (P=0.002), bone marrow blast count (P<1x10-4), number of cytopenias (P<1x10-4), revised IPSS cytogenetic category (P<1x10-4), hemoglobin concentration (P<1x10-4), neutrophil count (P<1x10-4) and platelet count (P<1x10-4). No difference in
Figure 1. Distribution of dose densities of all transfused patients in the interval preceding the 1-year landmark. Frequency: number of patients in each dose density ranging from >0 to 0.2 units per month to >6 units per mont.
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