Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome

H K G Garelius, W T Johnston, A G Smith, S Park, L de Swart, P Fenaux, A Symeonidis, G Sanz, J Čermák, R Stauder, L Malcovati, M Mittelman, A A van de Loosdrecht, C J van Marrewijk, D Bowen, S Crouch, T J M de Witte, E Hellström-Lindberg, H K G Garelius, W T Johnston, A G Smith, S Park, L de Swart, P Fenaux, A Symeonidis, G Sanz, J Čermák, R Stauder, L Malcovati, M Mittelman, A A van de Loosdrecht, C J van Marrewijk, D Bowen, S Crouch, T J M de Witte, E Hellström-Lindberg

Abstract

Background: The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower-risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals.

Objective: The aim of this study was to describe the usage and clinical impact of erythropoiesis-stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014.

Methods: The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need.

Results: ESA treatment (median duration of 27.5 months, range 0-77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65-1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post-ESA treatment transfusion was 6.1 months (IQR: 4.3-15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0-47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7-3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45-0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39-1.29, P = 0.27).

Conclusion: Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS.

Trial registration: ClinicalTrials.gov NCT00600860.

Keywords: MDS; Myelodysplasia; anaemia; haematology; haemoglobin.

© 2016 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

Figures

Figure 1
Figure 1
CONSORT diagram showing relationship between the groups of patients included in the different analyses presented in this study. The treatment pattern of erythropoiesis‐stimulating agents (ESAs) in different European countries was described for 1696 patients (773 ESA‐treated and 923 without ESA treatment). A total of 897 patients (484 ESA‐treated and 413 untreated) were retained for the propensity model group. The effect of ESA treatment on survival and disease progression was assessed only amongst the 860 analysed patients of the outcome group whose propensity scores for receiving ESA treatment were in the overlapping region of the propensity score distributions of treated and untreated patients. 1Patients with propensity scores outside the overlapping region denoted by the dashed lines in Fig. 4a. Hb, haemoglobin.
Figure 2
Figure 2
The use of erythropoiesis‐stimulating agents (ESAs) in a European low‐risk myelodysplastic syndrome (MDS) registry. (a) Proportion of registered patients receiving ESAs relative to the 2013 national gross domestic product (GDP) (source: http://www.imf.org/external/pubs/ft/weo/2014/02/weodata/index.aspx) showing no apparent relationship (bubble size is proportional to the number of registered patients shown in Table 1). (b) Most patients start ESA treatment relatively soon after diagnosis. (c) The haemoglobin (Hb) level at or near the start of treatment with ESAs amongst treated patients in participating countries was usually below the eligibility criteria of 10 g dL−1 (dashed line).
Figure 3
Figure 3
Comparison of time to first posterythropoiesis‐stimulating agent (ESA) treatment transfusion between ESA‐treated patients who did or did not respond to ESAs. (a) Time to first post‐ESA treatment transfusion was significantly improved amongst patients responding to ESA treatment compared to those not responding (HR 0.43, 95% CI: 0.32–0.57, P < 0.0001). (b) The response effect on time to first post‐ESA transfusion was evident when stratified by pre‐ESA transfusion experience (solid line versus long‐dashed line for untransfused patients and short‐dashed line versus dotted line for transfused patients).
Figure 4
Figure 4
The effect of erythropoiesis‐stimulating agent (ESA) treatment on survival and progression to acute myeloid leukaemia (AML). (a) Distribution of propensity scores for ESA‐treated (dark grey bars) and untreated (light grey bars) patients showing upper and lower bounds of the overlapping region (dashed lines). (b) Estimated effect of ESA treatment on survival (HR 0.82, 95% CI: 0.65–1.03, P = 0.09). (c) Estimated effect of ESA treatment on progression to AML (HR 0.88, 95% CI: 0.63–1.22, P = 0.43). (d) estimated effect of ESA treatment on survival amongst patients not receiving transfusions before ESA treatment [treated (solid line) versus untreated (short‐dashed line): HR 0.71, 95% CI: 0.49–1.03, P = 0.070] was greater than amongst those who had at least one pre‐ESA treatment transfusion [treated (long‐dashed line) versus untreated (dotted line): HR 0.93, 95% CI: 0.70–1.26, P = 0.67]. There was no significant statistical interaction between these effects (P = 0.26).

References

    1. Jädersten M, Montgomery S, Dybedal I, Porwit‐MacDonald A, Hellström‐Lindberg E. Long‐term outcome of treatment of anemia in MDS with erythropoietin and G‐CSF. Blood 2005; 106: 803–11.
    1. Jädersten M, Malcovati L, Dybedal I et al Erythropoietin and granulocyte‐colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol 2008; 26: 3607–13.
    1. Hellström‐Lindberg E, Gulbrandsen N, Lindberg G et al A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony‐stimulating factor: significant effects on quality of life. Br J Haematol 2003; 120: 1037–46.
    1. Nilsson‐Ehle H, Birgegård G, Samuelsson J et al Quality of life, physical function and MRI T2* in elderly low‐risk MDS patients treated to a haemoglobin level of ≥120 g/L with darbepoetin alfa ± filgrastim or erythrocyte transfusions. Eur J Haematol 2011; 87: 244–52.
    1. Park S, Grabar S, Kelaidi C et al Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G‐CSF: the GFM experience. Blood 2008; 111: 574–82.
    1. Kjeldsen L, Dybedal I, Hellström‐Lindberg E et al Guidelines for the diagnosis and treatment of Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia from the Nordic MDS Group 2014 [updated 1st of February 2014]. 2014.
    1. Killick SB, Carter C, Culligan D et al Guidelines for the diagnosis and management of adult myelodysplastic syndromes. Br J Haematol 2014; 164: 503–25.
    1. Malcovati L, Hellström‐Lindberg E, Bowen D et al Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet.. Blood 2013; 122: 2943–64.
    1. Greenberg PL, Attar E, Bennett JM et al Myelodysplastic syndromes: clinical practice guidelines in oncology. J Natl Compr Canc Netw 2013; 11: 838–74.
    1. Greenberg PL, Stone R, Bejar R et al Myelodysplastic Syndromes, Version 2.2015. J Natl Compr Canc Netw 2015; 13: 261–72.
    1. Kelaidi C, Beyne‐Rauzy O, Braun T et al High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower‐risk myelodysplastic syndromes: a phase II study by the GFM. Ann Hematol 2013; 92: 621–31.
    1. Balleari E, Clavio M, Arboscello E et al Weekly standard doses of rh‐EPO are highly effective for the treatment of anemic patients with low‐intermediate 1 risk myelodysplastic syndromes. Leuk Res 2011; 35: 1472–6.
    1. Park S, Kelaidi C, Sapena R et al Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112 patients. Leuk Res 2010; 34: 1430–6.
    1. Greenberg PL, Sun Z, Miller KB et al Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony‐stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood 2009; 114: 2393–400.
    1. de Swart L, Smith A, Johnston TW et al Validation of the revised international prognostic scoring system (IPSS‐R) in patients with lower‐risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry. Br J Haematol 2015; 170: 372–83.
    1. Cheson BD, Greenberg P, Bennett JM et al Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108: 419–25.
    1. Hellström‐Lindberg E, Ahlgren T, Beguin Y et al Treatment of anemia in myelodysplastic syndromes with granulocyte colony‐stimulating factor plus erythropoietin: results from a randomized phase II study and long‐term follow‐up of 71 patients. Blood 1998; 92: 68–75.
    1. Austin P. The use of propensity score methods with survival or time‐to‐event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med 2014; 33: 1242–58.
    1. Cole SR, Hernán M. Adjusted survival curves with inverse probability weights. Comput Methods Programs Biomed 2004; 75: 45–9.
    1. SSSI Inc . Software 14.1 User's Guide TEC, NC: 2015.
    1. Schemper M, Smith T. A note on quantifying follow‐up in studies of failure time. Control Clin Trials 1996; 17: 343–6.
    1. World Economic and Financial Surveys World Economic Outlook Database. . 2015.
    1. Germing U, Strupp C, Kündgen A et al No increase in age‐specific incidence of myelodysplastic syndromes. Haematologica 2004; 89: 905–10.
    1. Bernasconi P, Klercy C, Boni M, Cavigliano PM, Dambruoso I, Zappatore R. Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution. Am J Hematol 2013; 88: 120–9.
    1. Oliva EN, Nobile F, Alimena G et al Darbepoetin alfa for the treatment of anemia associated with myelodysplastic syndromes: efficacy and quality of life. Leuk Lymphoma 2010; 51: 1007–14.
    1. Goldberg SL, Chen E, Sasane M, Paley C, Guo A, Laouri M. Economic impact on US Medicare of a new diagnosis of myelodysplastic syndromes and the incremental costs associated with blood transfusion need. Transfusion 2013; 52: 2131–8.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren