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Novel dynamic outcome indicators and clinical endpoints in MDS
tudinal data from more than 2,738 patients with MDS, including 2,498 LR-MDS patients with a median age of 75 years, and a follow-up of up to 11 years, in 16 European countries plus Israel from 148 active sites (progress report as of March 1st 2020). Progression to HR-MDS/AML has occurred in 314 LR-MDS patients (13%), and 910 patients (33%) had died at time of last report. Data quality control, including monitoring of both clinical performance and data collection, has been implemented since the initiation of the EUMDS Registry. New prognostic indicators in LR-MDS have been identified as part of the MDS-RIGHT project (https://mds-europe.eu/right) funded by Horizon 2020, which started in May 2015 with an overarching aim of defining and implementing more (cost)-effective and safer interven- tions in LR-MDS.
Symptoms of anemia, the most common cytopenia in LR- MDS, accompanied by infectious or bleeding complications predominate in LR-MDS.5 About 25% of these patients develop AML, but most patients die from complications related to progressive BM failure and worsening cytopenias, and from their negative interaction with the extra-hemato- logic comorbidities presented by those patients of advanced age.6,7 Patients with LR-MDS are characterized by a notable reduction in health related quality of life (HRQoL).8,9 Moderate to severe anemia in older individuals (>60 years) leads to increased mortality both in patients with LR-MDS and in the general population.10,11 Likewise, anemia repre- sents an unfavorable prognosticator in possible pre-MDS conditions at advanced age.12 Improving response prediction will contribute to more effective and targeted use of the available health care interventions (HCI).13
According to the available evidence- and consensus- based therapeutic guidelines, current therapeutic interven- tions in LR-MDS include red blood cell transfusion (RBCT), erythropoietin stimulating agents (ESA), lenalidomide, and iron chelation therapy (ICT).11 For ESA, a predictive model has identified a group of patients characterized by serum erythropoietin (EPO) levels <500 mU/mL and a transfusion need of <2 units RBC/month with a favorable response compared to patients with higher EPO levels and/or higher numbers of RBCT/month.14 Treatment with lenalidomide is only recommended for a small subgroup of patients with partial loss of chromosome 5 (5q-) and RBCT-dependent anemia.15,16
The most frequently applied outcome parameter in this LR-MDS patient population is overall survival (OS). Analysis of the EUMDS Registry data showed that the cur- rently available risk scoring systems, including the IPSS-R, have a better prognostic capacity for disease progression to AML as compared with OS.2 We estimated that 58% of deaths in this population are not related to disease progres- sion, but are attributable to non-leukemic death.2,17 A high proportion of patients with LR-MDS have a median sur- vival of up to 5-10 years, meaning that clinical trials, the design of which identifies survival as a primary endpoint, may result in a potentially biased assessment of the effec- tiveness and evidence on the appropriate use of the avail- able interventions. Therefore, we have explored additional relevant outcome parameters in a Delphi survey, which could be used to circumvent the limited value of survival as primary endpoint in LR-MDS.18
Additional evidence is required to extend the existing prognostic and therapeutic response indicators in the older LR-MDS population, and to identify meaningful biological and clinical endpoints, including patient-reported outcome
measures and other patient-related factors. These new end- points may provide information on the effectiveness of the available therapeutic interventions early in the natural his- tory of the disease. These early indicators of treatment response may drive a more effective use of those interven- tions currently made.
Recent studies conducted on the large population of patients with LR-MDS included in the EUMDS Registry during its first 10 years of activity allowed validation of RBCT requirement and HRQoL as independent and mean- ingful outcome indicators and reliable measures of response to interventions, supporting their integration in the MDS- Core Outcome Set (COS) in this patient population.18 In addition, prospective studies based on the unbiased dataset of the EUMDS Registry allowed identification of early response determinants for targeted use of treatment modal- ities, including ESA, lenalidomide, and ICT.
Novel outcome indicators and meaningful early clinical endpoints in patients with lower-risk myelodysplastic syndromes
Kinetics of blood counts decrease is an independent outcome indicator in lower-risk myelodysplastic syn- dromes
The prognosis of LR-MDS is heterogeneous.2 Early iden- tification of patients at risk of rapid progression should rely on universal, affordable and non-invasive tools to gain acceptance in an older population often managed in com- munity care centers. All current MDS prognostic scores rely on steady-state assessments of cytopenias, i.e., hemoglobin (Hb)-levels, neutrophil or platelet counts on the day of ini- tial assessment.19 Time-dependent prognostic scores require repeated BM examinations, raising acceptability issues in this older patient population. To circumvent this limitation, we analyzed the prognostic role of the kinetics of cytope- nias during the first visit interval (6 months) following diag- nosis in LR-MDS patients prospectively included in the EUMDS registry.20 We performed a landmark analysis at the second visit, at around 6 months from diagnosis, to apply simple prognostic criteria in general clinical practice.
The results showed that a relative drop in platelets >25% at the 6-month landmark predicted shorter 5-year OS; 22% versus 49% in patients with platelet drop ≤ 25% (P<10-4), regardless of baseline IPSS-R or absolute platelet counts. Conversely, relative neutrophil drop >25% had no signifi- cant impact on OS. Subsequently, a classifier was built based on RBCT-dependency and relative platelet drop >25% at landmark. Patients with none (62%), either one of the two criteria (27%) or both criteria (11%) had 5-year OS of 53.3%, 32.7% and 9.0%, respectively (P<10-4) (Figure 1). Sensitivity analyses confirmed the applicability of this sim- ple classifier even when follow-up visits were planned at any time during the first ten months after diagnosis, thus capturing most situations encountered in daily practice.20
Red blood cell transfusion requirement is an independ- ent outcome indicator and freedom from transfusion a meaningful clinical endpoint in patients with lower-risk myelodysplastic syndromes
In order to extend existing outcome parameters in the older LR-MDS population,21 RBCT administration in the LR-MDS patients enrolled in the EUMDS Registry was
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