Risk stratification based on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome

Abstract

The incidence of myelodysplastic syndromes increases with age and a high prevalence of co-morbid conditions has been reported in these patients. So far, risk assessment in myelodysplastic syndromes has been mainly based on disease status. We studied the prognostic impact of comorbidity on the natural history of myelodysplastic syndrome with the aim of developing novel tools for risk assessment. The study population included a learning cohort of 840 patients diagnosed with myelodysplastic syndrome in Pavia, Italy, and a validation cohort of 504 patients followed in Duesseldorf, Germany. Information on comorbidity was extracted from detailed review of the patients' medical charts and laboratory values at diagnosis and during the course of the disease. Univariable and multivariable survival analyses with both fixed and time-dependent covariates were performed using Cox's proportional hazards regression models. Comorbidity was present in 54% of patients in the learning cohort. Cardiac disease was the most frequent comorbidity and the main cause of non-leukemic death. In multivariable analysis, comorbidity had a significant impact on both non-leukemic death (P=0.01) and overall survival (P=0.02). Cardiac, liver, renal, pulmonary disease and solid tumors were found to independently affect the risk of non-leukemic death. A time-dependent myelodysplastic syndrome-specific comorbidity index (MDS-CI) was developed for predicting the effect of comorbidity on outcome. This identified three groups of patients which showed significantly different probabilities of non-leukemic death (P<0.001) and survival (P=0.005) also in the validation cohort. Landmark survival analyses at fixed time points from diagnosis showed that the MDS-CI can better define the life expectancy of patients with myelodysplastic syndrome stratified according to the WHO-classification based Prognostic Scoring System (WPSS).Comorbidities have a significant impact on the outcome of patients with myelodysplastic syndrome. Accounting for both disease status by means of the WPSS and comorbidity through the MDS-CI considerably improves risk stratification in myelodysplastic syndromes.

Figures

Figure 1.

Relationship between MDS-CI category, risk of non-leukemic death and overall survival in the learning and validation cohorts of MDS patients. (A–B) Italian learning cohort; (A) Probability of overall survival according to time-dependent MDS-CI risk. (B) Probability of non-leukemic death according to time-dependent MDS-CI risk. (C–D); German validation cohort. (C) Probability of overall survival according to time-dependent MDS-CI risk. (D) Probability of non-leukemic death according to time-dependent MDS-CI risk.

Figure 2.

Risk of progression to a higher MDS-CI category during the course of the disease. Cumulative hazard of MDS-CI progression in the Italian cohort according to the presence or absence of transfusion dependency.

Figure 3.

Impact of the MDS-CI category with the WPSS risk groups. (A–D) Probability of overall survival of MDS patients stratified into time-dependent WPSS categories according to time-dependent MDS-CI. (A) Very low and low WPSS risk patients were plotted together in a single group. (B) Intermediate WPSS risk group. (C) High WPSS risk group. (D) Very high WPSS risk group.

Figure 4.

Schematic representation of the potential of combined use of WPSS, a disease-related prognostic scoring system, and MDS-CI in clinical decision making in MDS. It should be noted that we have recently shown that in MDS patients hemoglobin levels lower than 9 g/dL in males and 8 g/dL in females are independently related to reduced overall survival. Thus, severe anemia in MDS can be defined as a hemoglobin level below these thresholds.