Page 33 - 2020_11-Haematologica-web

Novel dynamic outcome indicators and clinical endpoints in MDS
evaluated the event-free survival (EFS) (a composite out- come, including non-fatal events related to cardiac and liver function, and transformation to AML or death) and safety of deferasirox versus placebo in low and intermediate-1-risk MDS patients. This trial demonstrated an EFS risk reduc- tion of 36.4% in the deferasirox arm (P=0.015), but the median OS in the deferasirox-treated arm did not differ (HR 0.83, 95%CI: 0.54-1.28; P=0.200) when compared with placebo. The results of the TELESTO study are in line with the EUMDS study, but the patients included may not rep- resent ‘real life’ older MDS patients with multiple comor- bidities, as reflected by the mean age of 61 years of the patients included in TELESTO study compared to the mean age of 70 years of the chelated patients in the EUMDS Registry study. Furthermore, low accrual rates and the cross-over to ICT after cessation of the placebo affected the statistical power of the TELESTO study.
Summary and concluding remarks
Available evidence suggests that in most patients with LR-MDS the risk of death is not related to disease progres- sion but is mainly attributable to non-leukemic death.2,17 In addition, a proportion of these patients have prolonged sur- vival that precludes the design of clinical trials adopting OS as a primary endpoint. These challenges have resulted in potentially biased assessment of the effectiveness and appropriate use of the available interventions in this patient population. The EUMDS Registry has identified novel meaningful outcome indicators and clinical endpoints, and reliable measures of response to HCI (Figure 4).
The results of our analysis indicate that RBCT density is strongly associated with a decreased OS, even at relatively
low dose densities. In addition, we observed that an early decrease in platelet count is an independent adverse prog- nostic indicator in LR-MDS, and combining relative platelet drop and transfusion dependency allows early identifica- tion of patients at risk of rapid progression, and may guide early therapeutic interventions, including allogeneic hematopoietic stem cell transplantation or experimental interventions. Taken together, these results indicate that regular RBCT requirement, early platelet count kinetics, and restriction in HRQoL are early independent and mean- ingful outcome indicators, and reliable measures of effec- tiveness of therapeutic interventions, evaluated in this set of studies. These findings support the integration of RBCT requirement and HRQoL in the general core outcome sets and in response criteria in patients with LR-MDS, and have important implications for clinical practice and the design of clinical endpoints. Our results strongly support the adop- tion of freedom from transfusion as a meaningful clinical endpoint in patients with LR-MDS.
Anemia is the main determinant of therapeutic interven- tion in patients with LR-MDS, and ESA are recommended as first-line treatment for patients with symptomatic ane- mia.10 The observational studies within the EUMDS Registry showed that the response rate, as well as the capacity of these agents to delay the onset of a regular RBCT need, is most pronounced in RBCT-naïve patients. These results identified early initiation of treatment with ESA as a major treatment response indicator, and indicate that ESA should be recommended in LR-MDS patients with symptomatic anemia before starting regular RBCT. After the onset of RBCT dependency, patients with LR- MDS are prone to long-term accumulation of iron.1,43 The EUMDS Registry studies provided evidence that elevated LPI levels are associated with reduced survival in RBCT
Figure 4. Overview of novel out- come indicators and clinical end- points identified in the European LeukemiaNet myelodysplastic syndromes (EUMDS) Registry. ESA: erythropoietin stimulating agents; LPI: labile plasma iron; NTBI: non-transferrin bound iron; TSAT: transferrin saturation; HRQoL: health related quality of life.
haematologica | 2020; 105(11)
2521