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Novel dynamic outcome indicators and clinical endpoints in MDS
older patients with chronic diseases that might not be reflected in the level of physical activity and relevant labora- tory parameters, including Hb levels.22 Preliminary data in HR-MDS patients suggest that these limitations may predict an unfavorable clinical outcome.8 However, definitive data on HRQoL in LR-MDS are rare. This EUMDS Registry proj- ect investigated the HRQoL-profile of LR-MDS patients at time of diagnosis as compared with age- and sex-matched reference groups from the general population.23 HRQoL was measured by the EuroQol-5 dimension (EQ-5D) score at the time of study enrolment.24,25 Population norms were used to assess the relative HRQoL of patients in comparison to those of the average person in the community.26
A significant proportion of MDS patients reported mod- erate or severe problems in the dimensions pain/discomfort (50%), mobility (41%), anxiety/depression (38%), and usual activities (36%). Clinically meaningful restrictions in the EQ-5D index, EQ-Visual Analog Scale (VAS) were observed significantly more often in older patients and in those with a high co-morbidity burden, low Hb levels or RBCT need (P<10-3). Relative to the EQ-5D index and EQ- VAS scores in the reference group, HRQoL was significantly lower for groups of patients with MDS who were older, female, or had increased comorbidities, low Hb-levels or RBCT dependence.23
Restrictions in distinct dimensions of the EQ-5D were also observed when compared with European reference populations, but this effect might (partly) be explained by the anemia in the MDS cohort, since older anemic patients in the general population also have a decreased HRQoL.11 Low Hb levels and RBCT need were associated both with a decreased EQ-5D index and a decreased EQ-VAS after adjustment for co-variables in this EUMDS-Registry study, further supporting the use of RBCT requirement as an indi- cator of loss of effectiveness of interventions and worsening outcome. In addition, transfusion-free survival appeared to be a meaningful clinical endpoint in patients with lower- risk MDS, as shown in the transfusion study.21 These find- ings have important implications for every-day clinical practice and the design of clinical endpoints.
Novel treatment-response indicators in lower risk myelodysplastic syndromes
Early initiation of treatment with erythropoietin stimulat- ing agents is an important response indicator and signif- icantly delays the onset of red blood cell transfusion dependency in patients with lower-risk myelodysplastic syndromes
Anemia of patients with LR-MDS and RBCT dependency have been associated with reduced HRQoL in several prospective trials27,28 and with reduced survival in retrospec- tive registry reports.10 Current guidelines recommend ESA as first-line treatment for LR-MDS patients with sympto- matic anemia.13 In recent studies, overall response rates var- ied between 38% and 66%, with a median response dura- tion of around 20 months.29 Retrospective analyses of large multi-center cohorts from different countries compared sur- vival in patients treated with ESA within clinical studies with untreated patients. Survival was markedly better in the group exposed to ESA with no difference in AML trans- formation.30,31
Within the EUMDS registry, the effects of ESA treatment on outcomes were explored amongst 1,696 unselected patients with anemia.32 To overcome potential confounding by non-random allocation of ESA treatment, proportional hazards regression models comparing time-to-event out- comes in treated and untreated patients were weighted by stabilized inverse probability of treatment weights based on the propensity of a patient to receive ESA treatment. Only patients with comparable propensity scores were included in the analyses to estimate the effects of ESA treat- ment on outcomes. The relationship between the effects of ESA and pre-ESA treatment transfusion status was explored using this model. A non-significant beneficial effect of ESA treatment on OS was estimated from the weighted regres- sion model comparing patients with comparable propensi- ty scores (hazard ratio [HR] 0.82, 95% confidence interval [CI]: 0.65-1.04; P=0.09). A non-significant estimate of a ben- eficial effect of ESA treatment on progression to AML or
Figure 3. Influence of dose density on progression-free survival (PFS) in a multivariate regression model adjusted for treatment with either erythro- poiesis-stimulating agent, iron chelation or lenalidomide. Dose density: average number of transfusions per month, cal- culated from start of transfu- sion until date of analysis.
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