***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Within the myelodysplastic syndrome ( MDS ) work package of the European LeukemiaNet , an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program . A systematic review of the literature was performed that included indexed original papers , indexed review s and educational papers , and abstract s of conference proceedings . Guidelines were developed on the basis of a list of patient- and therapy-oriented questions , and recommendations were formulated and ranked according to the supporting level of evidence . MDSs should be classified according to the 2008 World Health Organization criteria . An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity . The assessment of individual risk enables the identification of fit patients with a poor prognosis who are c and i date s for up-front intensive treatments , primarily allogeneic stem cell transplantation . A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and /or clinical ly relevant comorbidities and poor performance status . In these patients , the therapeutic intervention is aim ed at preventing cytopenia-related morbidity and preserving quality of life . A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use . The inclusion of patients into prospect i ve clinical trials is strongly recommended This phase 3 prospect i ve r and omized trial evaluated the efficacy and long-term safety of erythropoietin ( EPO ) with or without granulocyte colony-stimulating factor plus supportive care ( SC ; n = 53 ) versus SC alone ( n = 57 ) for the treatment of anemic patients with lower-risk myelodysplastic syndromes . The response rates in the EPO versus SC alone arms were 36 % versus 9.6 % , respectively , at the initial treatment step , 47 % in the EPO arm , including subsequent steps . Responding patients had significantly lower serum EPO levels ( 45 % vs 5 % responses for levels < 200 mU/mL vs > or = 200 mU/mL ) and improvement in multiple quality -of-life domains . With prolonged follow-up ( median , 5.8 years ) , no differences were found in overall survival of patients in the EPO versus SC arms ( median , 3.1 vs 2.6 years ) or in the incidence of transformation to acute myeloid leukemia ( 7.5 % and 10.5 % patients , respectively ) . Increased survival was demonstrated for erythroid responders versus nonresponders ( median , 5.5 vs 2.3 years ) . Flow cytometric analysis showed that the percentage of P-glycoprotein(+ ) CD34(+ ) marrow blasts was positively correlated with longer overall survival . In comparison with SC alone , patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses , similar survival , and incidence of acute myeloid leukemia transformation Treatment with erythropoietin ( epo ) may improve the anemia of myelodysplastic syndromes ( MDS ) in approximately 20 % of patients . Previous studies have suggested that treatment with the combination of granulocyte colony-stimulating factor ( G-CSF ) and epo may increase this response rate . In the present phase II study , patients with MDS and anemia were r and omized to treatment with G-CSF + epo according to one of two alternatives ; arm A starting with G-CSF for 4 weeks followed by the combination for 12 weeks , and arm B starting with epo for 8 weeks followed by the combination for 10 weeks . Fifty evaluable patients ( 10 refractory anemia [ RA ] , 13 refractory anemia with ring sideroblasts [ RARS ] , and 27 refractory anemia with excess blasts [ RAEB ] ) were included in the study , three were evaluable only for epo as monotherapy and 47 for the combined treatment . The overall response rate to G-CSF + epo  was 38 % , which is identical to that in our previous study . The response rates for patients with RA , RARS , and RAEB were 20 % , 46 % , and 37 % , respectively . Response rates were identical in the two treatment groups indicating that an initial treatment with G-CSF was not neccessary for a response to the combination . Nine patients in arm B showed a response to the combined treatment , but only three of these responded to epo alone . This suggests a synergistic effect in vivo by G-CSF + epo . A long-term follow-up was made on 71 evaluable patients from both the present and the preceding Sc and inavian study on G-CSF + epo .  Median survival was 26 months , and the overall risk of leukemic transformation during a median follow-up of 43 months was 28 % . Twenty patients entered long-term maintenance treatment and showed a median duration of response of 24 months . The international prognostic scoring system ( IPSS ) was effective to predict survival , leukemic transformation , and to a lesser extent , duration of response , but had no impact on primary response rates Previous studies have shown that approximately 40 % of patients with myelodysplastic syndrome ( MDS ) and anaemia respond to treatment with human recombinant granulocyte‐CSF ( G‐CSF ) plus erythropoietin ( epo ) . The present study was design ed to investigate pre‐treatment variables for their ability to predict erythroid responses to this treatment . 98 patients with MDS ( 30 RA , 31 RARS , 32 RAEB , five RAEB‐t ) were treated with a combination of G‐CSF ( 0.3–3.0 μg/kg/d , s.c . ) and epo ( 60–300 U/kg/d , s.c . ) for at least 10 weeks . Minimum criteria for erythroid response was a 100 % reduction of red blood cell ( RBC ) transfusion need or an increase in haemoglobin level of 1.5 g/dl . 35 patients ( 36 % ) showed responses to treatment . Medium duration of response was 11–24 months . In multivariate analysis , serum erythropoietin levels and initial RBC‐transfusion need retained high statistical significance ( P < 0.01 ) . Using pre‐treatment serum epo levels as a ternary variable ( < 100 , 100–500 or > 500 U/l ) and RBC transfusion need as a binary variable ( < 2 or 2 units per month ) , the analysis provided a predictive score for erythroid response . This score divided patients into three groups : one group with a high probability of erythroid responses ( 74 % ) , one intermediate group ( 23 % ) and one group with poor responses to treatment ( 7 % ) . This predictive scoring system could be used in decisions regarding use of these cytokines for treating the anaemia of MDS , both for defining patients who should not be given the treatment and for selecting patients for inclusion in prospect i ve trials Abstract Background : Current guidelines support the use of erythropoiesis-stimulating agents for the treatment of anemia associated with low-risk myelodysplastic syndromes ( MDS ) . Design and methods : Single-arm , open-label , multi-center , phase 2 trial that evaluated the efficacy and safety of darbepoetin alfa ( DA ) in patients with low or intermediate-risk MDS , hemoglobin < 100 g/L , erythropoietin ( EPO ) levels < 500 IU/L and transfusion requirements < 2 units/month over the preceding 2 months . Erythroid response ( major [ MaR ] or minor [ MiR ] ) and fatigue ( Functional Assessment of Cancer Therapy – Fatigue [ FACT-F ] ) were evaluated at 8 , 16 and 24 weeks . DA was initiated at 300 μg weekly . For patients who did not achieve MaR by 8 weeks , filgrastim 300 μg weekly was added . Clinical trial registration : clinical trials.gov identifier : NCT01039350 . Results : Forty-four patients ( 72.7 % transfusion independent ) were included . Median age was 76.0 years ( range 41.3–92.4 ) , 54.5 % were male , and 90.9 % presented ECOG Status ( 0–1 ) . Eighteen patients received filgrastim . An erythroid response was achieved by 31 of 44 patients ( 70.5 % ) at week 8 ( 47.7 % MaR , 22.7 % MiR ) , 31 of 44 patients ( 70.5 % ) at week 16 ( 61.4 % MaR , 9.1 % MiR ) , and 32 of 44 patients ( 72.7 % ) at week 24 ( 61.3 % MaR , 11.4 % MiR ) . Mean ( 95 % CI ) change in FACT-F at week 24 was 3.61 ( 0.72 to 6.51 ) . Baseline EPO levels < 100 IU/L were a predictive factor of response . DA was well tolerated . Four mild ( two iron deficiencies , flu syndrome and headache ) and one fatal ( thromboembolic event ) adverse events were considered related to darbepoetin alfa . Conclusions : A fixed dose of 300 μg of darbepoetin alfa weekly ( with or without filgrastim ) seems to be an effective and safe treatment for anemic patients with low or intermediate-risk MDS , low transfusion burden and EPO levels < 500 IU/L. Results may not be extrapolable to unselected MDS patients Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more The myelodysplastic syndromes ( MDSs ) are heterogeneous with respect to clinical characteristics , pathologic features , and cytogenetic abnormalities . This heterogeneity is a challenge for evaluating response to treatment . Therapeutic trials in MDS have used various criteria to assess results , making cross- study comparisons problematic . In 2000 , an International Working Group ( IWG ) proposed st and ardized response criteria for evaluating clinical ly significant responses in MDS . These criteria included measures of alteration in the natural history of disease , hematologic improvement , cytogenetic response , and improvement in health-related quality of life . The relevance of the response criteria has now been vali date d prospect ively in MDS clinical trials , and they have gained acceptance in research studies and in clinical practice . Because limitations of the IWG criteria have surfaced , based on practical and reported experience , some modifications were warranted . In this report , we present recommendations for revisions of some of the initial criteria BACKGROUND AND OBJECTIVE Anemia leading to transfusion is probably the most important problem in patients with myelodysplastic syndromes ( MDS ) .  Human recombinant erythropoietin ( rHuEpo ) and granulocyte colony-stimulating factor ( G-CSF ) have been used to treat patients with anemia of MDS , but fewer than 50 % respond . The aim of this work was to evaluate the benefit of rHuEpo + /- G-CSF treatment and to isolate the response predictive variables in a group of selected patients with MDS . DESIGN AND METHODS A non-r and omized multicenter trial was carried out in 32 patients with MDS . The inclusion criteria were age > = 18 years , refractory anemia ( RA ) or refractory anemia with ringed sideroblasts , Hb < = 100 g/L or receiving transfusions and serum erythropoietin < = 250 U/L. These patients were treated with subcutaneous rHuEpo ( 300 U/kg ) three times a week for 8 weeks . In the case of partial response ( PR ) or no response ( NR ) subcutaneosly administered G-CSF ( 1 microg/kg ) three times a week was added to the rHuEpo for 8 more weeks . If the patient achieved complete response ( CR ) or PR in the second phase , he was included in a follow-up phase of 24 weeks in which the dose of growth factors was tapered down . Several variables , including the score published by the Sc and inavian-American group , were used as possible predictive variables . RESULTS An erythroid response was observed in 16 patients ( 50 % ) ; in 12 it was a CR and in 4 it was a PR . During the period of rHuEpo administration , 7 CR and 4 PR ( 34.4 % ) were documented . Of the 14 patients in whom G-CSF was added to rHuEpo , 7 ( 50 % ) responded ( 3 CR and 4 PR ) . No major side-effects associated with growth factors were observed . The multivariate analysis showed that of the different variables evaluated only the Sc and inavian-American response score was significant with a relative probability of response of 11.8 ( 95 % confident intervals : 2.5 - 53 ) when this score was > + 1 ( 77 % of cases responded ) . In contrast , when this score was < = 1 only 15 % of the cases responded . INTERPRETATION AND CONCLUSIONS Use of the Sc and inavian-American response score is to be recommended in a patient-oriented approach to treating MDS cases with the Epo and G-CSF . Treatment with rHuEpo and G-CSF is safe , its main drawback being its cost . However , a long-term study evaluating the regimen 's cost-benefit ratio is warranted Darbepoetin ( DAR ) , with or without granulocyte colony-stimulating factor ( G-CSF ) , has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome ( MDS ) , but its effects on quality of life ( QoL ) and exercise functioning are less well established . In this phase 
    Output:
    
Our analysis supports an additional efficacy of G-CSF added to low-/st and ard-dose ESA , but the available data remains controversial , if G-CSF is added to full-dose ESA