Elsevier

The Lancet Oncology

Volume 16, Issue 15, November 2015, Pages 1506-1514
The Lancet Oncology

Articles
Prognostic value of self-reported fatigue on overall survival in patients with myelodysplastic syndromes: a multicentre, prospective, observational, cohort study

https://doi.org/10.1016/S1470-2045(15)00206-5Get rights and content

Summary

Background

The clinical presentation of myelodysplastic syndromes is highly variable and so accurate prediction of outcomes in these patients is crucial. We aimed to assess whether self-reported fatigue severity predicts overall survival beyond gold-standard prognostic indices in patients with higher-risk myelodysplastic syndromes.

Methods

We did a multicentre, prospective, observational, cohort study of patients from 37 centres in Europe, USA, and east Asia. Adults (≥18 years) with myelodysplastic syndromes were consecutively enrolled within 6 months of diagnosis with an intermediate-2-risk or high-risk score according to the International Prognostic Scoring System (IPSS). Patients were enrolled irrespective of older age, comorbidities, performance status, and progression from a lower IPSS risk score category. All patients had to complete a quality of life assessment at baseline. With use of univariate and then multivariate Cox proportional hazards regression analysis, we constructed a multivariate model of how prognostic variables, including IPSS and fatigue score from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire–core 30, predicted overall survival. The primary endpoint was overall survival by baseline self-reported fatigue scale ratings. This study was registered with ClinicalTrials.gov, number NCT00809575.

Findings

Between Nov 10, 2008, and Aug 13, 2012, we enrolled 280 patients with a median age of 71 years (IQR 64–77). The median follow-up was 15 months (IQR 8–27), and the last patient was assessed Feb 16, 2015. The median overall survival from diagnosis was 17 months (95% CI 15–19). In univariate analysis, the baseline factors that were significantly associated with reduced overall survival were increasing age, transfusion dependency (defined as having received at least one red blood cell transfusion every 8 weeks over a period of 4 months), Eastern Cooperative Oncology Group (ECOG) performance status of two or more, increased white blood cell count, high-risk IPSS score, and higher self-reported fatigue severity. In multivariate analysis, baseline factors independently associated with reduced overall survival were high-risk IPSS score (hazard ratio [HR] 2·525, 95% CI 1·357–4·697; p=0·0035) and a higher score for fatigue (1·110, 1·040–1·170, for every ten points of fatigue deterioration; p=0·0007). In further multivariate models for survival, including either the WHO-based prognostic scoring system or the revised version of the IPSS classification, fatigue remained a statistically significant independent prognostic factor with a HR of 1·120 (1·050–1·180, p=0.0003) and a HR of 1·130 (1·060–1·190, p=0·0002), respectively.

Interpretation

In patients with newly diagnosed higher-risk myelodysplastic syndromes, self-reported fatigue severity provides prognostic information for survival independent from gold-standard risk classifications. Our findings suggest that fatigue assessment should be included in routine diagnostic investigation for these patients and considered as a standard baseline stratification factor in future randomised controlled trials.

Funding

Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL).

Introduction

Myelodysplastic syndromes are clonal disorders of haemopoietic stem cells and are characterised by ineffective haemopoiesis resulting in blood cytopenias. The clinical presentation of myelodysplastic syndromes is highly variable, ranging from patients with indolent disorders, who have a life expectancy similar to that of the general population, to symptomatic forms with a poor prognosis and high risk of progression to acute myeloid leukaemia.1 Given the large variability in the course of the disease, the ability to predict outcomes accurately for individual patients, at the time of diagnosis, is a cornerstone of myelodysplastic syndromes management.2

A key improvement in the clinical management of patients with myelodysplastic syndromes was the development of the International Prognostic Scoring System (IPSS).3 Assessed features have both clinical and laboratory variables, including: percentage of bone marrow blasts, number of peripheral cytopenias (ie, haemoglobin, neutrophil cell counts, and platelet counts), and cytogenetic abnormalities. According to the IPSS, each of these variables has a relative risk score that can be combined to stratify patients with myelodysplastic syndromes into four distinctive risk groups—low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk.3 Patients with intermediate-2 or high risk (ie, higher-risk patients) have a poorer prognosis than have those in other catagories.1 In these higher-risk patients, accurate prediction of survival is crucial to provide personalised treatment strategies and to avoid inappropriate aggressive therapies, and related toxic effects, in patients with a short life expectancy.4

Research in context

Evidence before this study

Evidence from other studies of patients with cancer suggests that self-reported health status parameters, such as symptoms or functional limitations, could provide independent prognostic information for survival. However, data come mainly from secondary analysis of randomised controlled trials of solid tumours. This issue has not been investigated with hypothesis-driven prospective studies in patients with myelodysplastic syndromes.

We searched PubMed for full-length articles at the time of protocol writing using the following keywords: “myelodysplastic”, “myelodysplasia” AND “fatigue” or “quality of life” or “health status” AND survival AND prognosis. We found no reports investigating the prognostic value of fatigue for overall survival in patients with myelodysplastic syndromes. After completion of our study, we repeated the search on PubMed using the same searching strategy for studies published up to April, 2015; 101 records were retrieved. We found one prospective study investigating the prognostic value of self-reported fatigue in a mixed sample of acute myeloid leukaemia and myelodysplastic syndromes. Although this study provided important insights on this topic, the prognostic value of fatigue was not tested against validated prognostic indices for myelodysplastic syndromes.

Added value of this study

Self-reported pretreatment fatigue severity provided independent prognostic information for survival in patients with higher-risk myelodysplastic syndromes beyond gold-standard prognostic indices, including the International Prognostic Scoring System (IPSS) classification, the WHO-based prognostic scoring system, and the revised version of the IPSS classification.

Implications of all the available evidence

Physicians should assess pretreatment fatigue severity during the initial diagnostic investigation because it provides independent prognostic information for survival. Our findings lay the groundwork for the future elaboration of a patient-centred prognostic index in patients with higher-risk myelodysplastic syndromes that would enable more accurate stratification of patients into different risk groups based on self-reported fatigue.

The IPSS is the most widely used prognostic index in clinical practice and by health regulatory authorities for approval of drugs,1, 2 and major international guidelines recommended its use.5 In a continued effort to improve physicians' ability to make accurate prognoses in patients with myelodysplastic syndromes, two other indices were also recently developed and are important in the management of myelodysplastic syndromes5—the WHO-based prognostic scoring system (WPSS)6 and a revised version of the IPSS classification (IPSS-R).7

A novel finding in the science of prognostication in oncology has been that patient's self-reported health status parameters, such as symptoms or functional limitations, could also provide prognostic information for survival.8 However, most studies investigating patient-reported outcomes were done on patients with solid tumours who were enrolled in randomised controlled trials,9 possibly limiting appraisal of how findings are applicable in real-life settings. Quality of life for patients with myelodysplastic syndromes is poor10 and, at diagnosis, they frequently present with fatigue that also interferes with their ability to function in daily life.11, 12, 13 We therefore postulated that fatigue would provide independent prognostic information for survival. We aimed to investigate whether self-reported fatigue severity in newly diagnosed patients with myelodysplastic syndromes with higher-risk disease would predict survival.

Section snippets

Study design and participants

In this international, prospective, cohort, observational study, we consecutively enrolled adults (≥18 years) from 37 centres in Austria, Belgium, China, Czech Republic, France, Italy, Germany, Taiwan, UK, and USA (appendix). Patients were approached in the hospital and invited to participate by their treating physician. Patients were diagnosed according to the WHO classification.14 Inclusion criteria have been reported previously.15 Briefly, patients were eligible if they were diagnosed with

Results

From Nov 10, 2008, to Aug 13, 2012, we consecutively enrolled 280 patients with a median age of 71 years (IQR 64–77; table 1). Median follow-up time was 15 months (IQR 8–27), with the last patient assessed on Feb 16, 2015.

Median overall survival was 17 months (95% CI 15–19). During follow-up, 126 (61%) of 206 patients died in the IPSS intermediate-2-risk group and 53 (72%) of 74 patients died in the IPSS high-risk group. 174 (62%) patients had received at least one red blood cell transfusion

Discussion

Self-reported fatigue severity provided independent prognostic information for survival beyond gold-standard prognostic indices in newly diagnosed patients with higher-risk myelodysplastic syndromes. Our results provide a strong evidence-based rationale for the need to collect patient's self-reported fatigue routinely in diagnostic investigation of patients with myelodysplastic syndromes with intermediate-2 and high-risk IPSS risk scores.

Our data might suggest that patients themselves are

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