Erythropoietic stimulating agents (ESAs) are the mainstay treatment oflower risk anemic patients with myelodysplastic syndromes (MDS),with reported response rates of 27%-50%1–3 and response durationsthat range from 12–24 months.4 In case control studies, the use ofESAs in lower risk MDS patients is associated with improved overallsurvival4–6 primarily in lower risk patients who
respond to ESA therapy.In a randomized controlled trial compared with best supportive care, ESA use was associated with improved quality of life and improvedoverall survival in responding patients.7The heterogeneity in responsiveness to ESA has led to efforts todevelop tools that allow identification of patients most and least likelyto respond. Factors identified as predictive of response include lowerendogenous erythropoietin (EPO) levels, marrow blasts<10%, international
prognostic scoring system (IPSS) low and int-1, French AmericanBritish (FAB) MDS subtype refractory anemia, normal karyotype, transfusionindependence, and short duration of disease.8 The most commonlyemployed predictive score for ESA (1 granulocyte colonystimulating factor [G-CSF]) use is that of the Nordic group, a weightedscoring system developed in 1997 comprising 2 elements: erythropoietinlevel (< 100 IU/L, 100–500 IU/L, and>500 IU/L) and 2 levels ofred blood cell (RBC) transfusion dependence (< 2 units vs _2 u/4weeks). The response criteria in
Scandinaviaincluded complete andpartial responses (CR1PR). The model, derived from 98 evaluablepatients divided patients into 3 predictive risk categories for responsesof 7%, 25%, and 74%.9 This scoring system has been validated by othergroups.10–12 Importantly, as a result of this scoring system, patientswith endogenous erythropoietin levels greater than 500 IU/L are
rarelyoffered ESA trials and ESA’s are typically offered to patients withscores of 21 and higher (Overall response rate, ORR, 25%-74%). Clinicalpredictive scores that include
aberrantimmunophenotype on myeloidblasts have been proposed13 but these were developed in smallgroups of patients and are limited in general application by the necessityfor flow cytometric analysis of a recent bone marrow specimen.Recently, alternative ESA predictive scores based on the IPSSRevised(IPSS-R), serum erythropoietin (EPO), and ferritin concentrations14
or based on the IPSS and serum EPO concentration alone15were proposed and are summarized in Supporting Information TableS5.In this study, using a large pooled dataset of ‘real life’ patients, weaimed to validate these 3 scoring systems and to develop a novel predictiveESA score to refine the predictive power of the Nordic score.We also hoped to identify a patient subgroup whose expected ESA
response rate was<10%, for whom an ESA was likely to be futile. 2 | METHODS
Data for this study were drawn from 3 large, prospectively collecteddatabases, Myelodysplastic Syndromes Registry of Canada (MDSCAN),Fondazione Italiana Sindromi Mielodisplastiche (FISM), andGruppo ROmano Mielodisplasie (GROM). MDS-CAN is a national Canadian Registry comprising 15 centers and 617 patients enrolledsince 2008 and previously described.16 The
Fondazione Italiana SindromiMielodisplastiche (FISM) Registry stems from the framework ofthe Italian Network of regional MDS registries and is the largest ItalianMDS Registry, with more than 80 active centers and almost 5000patients enrolled since 1999. Gruppo ROmano Mielodisplasie (GROM)registry retrospectively collected data on patients diagnosed with MDSfrom January 2002 to December 2010 that were recruited in 11 HematologicalCenters (5 University hospitals and 6 community-based hospitals)located in the metropolitan area of Rome, Italy.In all 3 registries, patient consent and institutional research ethicsboard approvals were obtained. MDS was diagnosed according to theWorld Health Organization (WHO) 2008 classification, and patientswere risk stratified according to both the IPSS and IPSS-R.17–19 Additionaldemographic and clinical variables captured included age, gender,time from diagnosis until ESA use, red blood cell transfusion requirements,use of G-CSF, serum lactate dehydrogenase (LDH), and ferritin
levels.Patients selected for inclusion in the analysis had received anadequate trial of ESA therapy, defined as a minimum of erythropoietin40 000 IU/week or darbepoietin 300–500 ug/q2–3 weeks, for a minimumduration of 12 weeks. Patients treated concurrently with G-CSFwere retained in the analysis. RBC transfusion therapy was administered
according to consensus-based guidelines.20
2.1 | Response criteriaErythroid response was strictly assigned according to International
Working Group (IWG) 2006 criteria.21 The response rates according tothe Nordic score, IPSS-R based, and MDS-CAN ESA scores wererecorded.11,14,15 Transfusion independence was definedas either<1RBC unit every 8 weeks, over a period of 16 weeks as defined by theWHO-based
Prognostic Scoring System (WPSS)17 or<2 units of bloodevery 4 weeks according to the Nordic score.9,17 If serial ESA’s wereused (eg, erythropoietin followed by darbepoetin), response wasassigned based on the first ESA eliciting the response.2.2 | Statistical evaluationPatient characteristics were summarized using median and interquartileranges (IQR) for continuous variables, and proportions for categoricalvariables. To compare ESA overall response (yes vs no), the Wilcoxonrank-sum test or Fisher’s exact test was used for continuous or categoricalvariables, respectively. A 2-sided P-value<.05 was consideredstatistically significant. To search for factors predictive of ESAresponse, univariate logistic regression analysis was used to create aprediction model. The R2 value was applied as a measure of goodnessof-fit, and indicated the proportion of the overall response variationthat could be explained by the predictive factor(s). A larger
R2indicateda better model fit. Natural log transformation was applied to somecovariates to normalize their distribution. Covariates with a P value<.10 and the highest R2 obtained from univariate analysis wereincluded in the backward stepwise selection procedure of the
