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Turkish Journal of Hematology logoLink to Turkish Journal of Hematology
. 2023 May 29;40(2):92–100. doi: 10.4274/tjh.galenos.2023.2022.0437

Long-Term Efficacy of Erythropoiesis-Stimulating Agents in Patients with Low-Risk or Intermediate-1-Risk Myelodysplastic Syndrome: Multicenter Real-Life Data

Eritropoezi Stimüle Edici Ajanların Düşük Riskli veya Orta-1 Riskli Myelodisplastik Sendromlu Hastalarda Uzun Dönem Tedavi Etkinliğinin Değerlendirilmesi: Çok Merkezli Gerçek Yaşam Verisi

Müzeyyen Aslaner Ak 1,*, Ayfer Gedük 2, İbrahim Halil Acar 3, Merve Gökçen Polat 2, Cenk Sunu 4, Ali Zahit Bolaman 5, Tuğba Hacıbekiroğlu 4, Birol Güvenç 3, Şehmus Ertop 1
PMCID: PMC10240155  PMID: 36799095

Abstract

Objective:

This study was undertaken to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndrome (MDS) in a real-life setting.

Materials and Methods:

A total of 204 patients with low-risk or intermediate-1-risk MDS who received epoetin alfa or darbepoetin alfa were included. Hemoglobin levels and transfusion needs were recorded before treatment and at 12 months, 24 months, 36 months, and 48 months of treatment.

Results:

At the 36-month (p=0.025) and 48-month (p=0.022) visits, epoetin alfa yielded significantly higher hemoglobin levels compared to darbepoetin alfa. Transfusion needs were also significantly lower with epoetin alfa compared to darbepoetin alfa at 24 months (p=0.012) and in the low-risk group compared to the intermediate-risk group at 24 months (p=0.018), 36 months (p=0.025), and 48 months (p<0.001). Treatment response rates at the 24-month, 36-month, and 48-month visits in the epoetin alfa (43.0%, 33.6%, and 27.1%), darbepoetin alfa (29.9%, 22.7%, and 16.5%), low-risk (39.3%, 30.0%, and 26.0%), and intermediate-risk (29.6%, 24.1%, and 11.1%) groups were lower than those obtained at 12 months, and the values differed significantly for the 36-month and 48-month visits with values ranging from p<0.05 to p<0.001.

Conclusion:

This real-life long-term ESA extension study investigated the clinical efficacy of epoetin alfa and darbepoetin alfa for up to 48 months, revealing that treatment efficacy reached a plateau starting from the 24th month of therapy with a continuing decrease in treatment response rates regardless of treatment type, risk status, or gender. Nonetheless, significantly higher hemoglobin levels and marked improvement in transfusion needs were evident in epoetin-treated patients compared to darbepoetin-treated patients and in the low-risk group compared to the intermediate-risk group.

Keywords: Myelodysplastic syndrome, Low-risk, Intermediate-1-risk, Epoetin alfa, Darbepoetin alfa, Long-term, Treatment response, Duration of response, Transfusion dependence

Introduction

Epoetin alfa (short-acting) and darbepoetin alfa (long-acting) are commonly used erythropoiesis-stimulating agents (ESAs) in clinical practice for the treatment of anemia in patients with low-risk or intermediate-1-risk myelodysplastic syndrome (MDS) to reduce the transfusion requirements and transfusion-related risks [1,2,3,4,5]. However, the ESA response rates in routine practice may differ from those reported in clinical trials with the use of higher doses of ESAs [6,7]. The value of continuing ESAs in the absence of an early response also remains unclarified due to investigations of response rates rather than durations of response in most previous ESA studies [3,8,9,10,11].

We previously reported the comparative efficacy of 12-month epoetin alfa and darbepoetin alfa treatments in improving hemoglobin levels and reducing transfusion needs in patients with low-risk or intermediate-1-risk MDS in a real-life setting [12]. The present extension study aims to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in terms of the rate and durability of treatment response and transfusion dependence for up to 48 months in patients with low-risk or intermediate-1-risk MDS in a retrospective real-life setting.

Materials and Methods

Study Population

A total of 204 patients newly diagnosed with low-risk or intermediate-1-risk MDS who received ESA treatment with epoetin alfa (Eporon®, Dem Pharmaceuticals; maintenance: 75-300 U/kg per week; maximum dose: 900 U/kg per week) or darbepoetin alfa (Aranesp®, Amgen Pharmaceuticals; maintenance: 0.13-0.35 µg/kg per week; maximum dose: 150 µg per week) after the diagnosis were included in this retrospective multicenter, non-interventional hospital registry study. Pretreatment erythropoietin (EPO) levels of <500 IU/mL and the presence of hemoglobin levels of <10 g/dL with or without a need for ≥2 units of erythrocyte suspension transfusion per month were the inclusion criteria of the study. Patients with high-risk MDS, acute myeloid leukemia, EPO levels of >500 IU/mL, hemoglobin levels of >12 g/dL, anemia related to iron deficiency or chronic disease, uncontrolled hypertension or chronic kidney disease, or any MDS treatments other than ESAs were excluded.

Written informed consent was obtained from each patient following a detailed explanation of the objectives and protocol of the study, which was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and approved by the relevant institutional ethics committee (date of approval: 01/12/2021; protocol no: 2021/23).

Data Collection

Data on baseline characteristics including patient demographics, EPO and hemoglobin levels, transfusion needs, and type of ESA treatment were recorded. Data on hemoglobin levels and transfusion needs were recorded in the pretreatment period as well as at four consecutive visits (12-month, 24-month, 36-month, and 48-month visits) after the onset of treatment. Treatment response was evaluated in subgroups according to ESA treatments (epoetin alfa vs. darbepoetin alfa), risk groups (low vs. intermediate risk), and genders (female vs. male).

MDS Diagnosis, Risk Groups, and Treatment Response

MDS risk stratification and assessments of response to treatment were performed as previously described [13,14].

ESA Treatments

Treatment doses for epoetin alfa (Eporon®, Dem Pharmaceuticals; initial dose of 50-150 U/kg per week, maintenance: 75-300 U/kg per week; maximum dose: 900 IU/kg per week) and darbepoetin alfa (Aranesp®, Amgen Pharmaceuticals; initial dose of 0.25-0.75 µg/kg per week; maintenance: 0.13-0.35 µg/kg per week; maximum dose: 150 µg/kg per week) were determined in accordance with the Turkish Ministry of Health’s Health Implementation Directive.

Treatment was continued until the loss of response in any cases. For patients with failure to achieve treatment response or those with partial erythroid response (50% reduction in transfusion need) after at least 8 weeks of regular treatment, dose increments were applied. For patients who failed to achieve sufficient treatment responses despite the maximum dose of ESA, treatment was discontinued at weeks 16-24. Cross-over was not allowed in accordance with local regulations. Patients with low serum ferritin levels under treatment received iron supplementation therapy.

Statistical Analysis

Statistical analysis was performed using MedCalc Statistical Software version 12.7.7 (MedCalc Software, Ostend, Belgium; http://www.medcalc.org; 2013). Cochran’s Q test and the post hoc McNemar test with Bonferroni correction were used for comparisons of categorical data, while numerical data were analyzed using the Student t-test and Mann-Whitney U test for variables with normal distribution and non-normal distribution, respectively. Change over time was analyzed via repeated-measures ANOVA with Bonferroni corrections. Data were expressed as mean ± standard deviation, minimum-maximum, and percentage (%) as appropriate. Values of p<0.05 were considered statistically significant.

Results

Baseline Characteristics

No significant difference was noted between treatment groups in terms of baseline characteristics (Table 1).

Table 1. Baseline characteristics.

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Hemoglobin Levels

In both the epoetin alfa and darbepoetin alfa groups, hemoglobin levels were significantly higher at the 12th month compared to pretreatment levels (p<0.001 for each). Hemoglobin levels at later visits (24, 36, and 48 months) showed no significant changes from the baseline hemoglobin levels (Table 2).

Table 2. Hemoglobin levels according to treatment and gender.

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Epoetin alfa yielded significantly higher hemoglobin levels compared to darbepoetin alfa at the 36-month (p=0.025) and 48-month (p=0.022) visits (Table 2, Figure 1).

Figure 1.

Figure 1

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Marginal cut-off values for hemoglobin according to treatment type and risk groups.

mo: month.

Hemoglobin levels were significantly higher in the low-risk group compared to the intermediate-1-risk group in the pretreatment period and at each follow-up visit, with significance values ranging from p=0.014 to p<0.001 (Table 3, Figure 1).

Table 3. Hemoglobin levels according to risk groups and genders.

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In each risk group, hemoglobin levels were significantly increased from baseline at the 12-month visit regardless of gender (Table 3).

Transfusion Needs

A significant decrease in transfusion needs from the baseline was evident at each follow-up visit in the epoetin alfa group (p<0.001 for each visit) and in the low-risk group (from p<0.01 to p<0.001). In the darbepoetin alfa and intermediate-1 risk groups, there was no significant change from baseline in transfusion needs during the follow-up visits (Table 4).

Table 4. Transfusion needs according to treatment and risk groups.

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Transfusion needs were significantly lower in the epoetin alfa group compared to the darbepoetin alfa group at 24 months (p=0.012) and in the low-risk group compared to the intermediate-1-risk group at 24 months (p=0.018), 36 months (p=0.025), and 48 months (p<0.001) (Table 4).

Percentage of Patients with Treatment Response (≥1.5 g/dL Increase in Hemoglobin)

The 24-month, 36-month, and 48-month treatment response rates in the epoetin alfa (43.0%, 33.6%, and 27.1%), darbepoetin alfa (29.9%, 22.7%, and 16.5%), low-risk (39.3%, 30.0%, and 26.0%), and intermediate-1-risk (29.6%, 24.1%, and 11.1%) groups were lower than the 12-month response rates, but the decrease was only significant at the 36-month and 48-month visits (from p<0.05 to p<0.001). The lowest response rates were achieved at 48 months in the darbepoetin alfa and intermediate-1-risk groups (p<0.05 for each) (Table 5).

Table 5. Treatment response (≥1.5 g/dL increase in hemoglobin) rates from baseline and from the previous visit during long-term follow-up.

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Discussion

This real-life long-term ESA extension study revealed that treatment efficacy reached a plateau starting from the 24th month of therapy with a continuing decrease in treatment response rates regardless of treatment type, risk status, or gender. Nonetheless, hemoglobin levels were significantly higher alongside more prominent improvement in transfusion dependency and a slower decrease in treatment response rates from baseline in epoetin-treated patients compared to darbepoetin-treated patients as well as in the low-risk group compared to the intermediate-1-risk group during long-term follow-up.

In this study, the treatment response rates at the 24-month, 36-month, and 48-month visits in the epoetin alfa (43.0%, 33.6%, and 27.1%) and darbepoetin alfa (29.9%, 22.7%, and 16.5%) groups were lower than the 12-month response rates in each group (44.9% and 46.4%, respectively). These findings are consistent with the overall response rates ranging from 20% to 40% and durations of response ranging from 10 to 24 months reported  in previous studies on ESAs, considering the refractoriness rate for ESAs to be approximately 40%-50% after 2 years of treatment [6,10,11]. Specifically, multicenter studies of epoetin-treated patients with MDS revealed response rates of approximately 30%-50% with durations of 12-24 months [1,6,15,16,17,18,19,20,21], while single-arm darbepoetin alfa studies reported durations of response ranging from 1 to 36 months [17,22,23,24]. Prospective observational studies also revealed similar response rates for patients treated with epoetin alfa and darbepoetin alfa, despite differences in median response durations obtained with epoetin alfa (7.5-15 months) and darbepoetin alfa (9.7 months) [1,25,26,27].

In addition, in an international pooled analysis of 1698 low-risk MDS patients treated with ESAs, the authors reported that most responses occurred within 3 months, with a median duration of response of 17 months [28]. In a meta-analysis of 10 studies of the efficacy and safety of darbepoetin involving a total of 647 darbepoetin-treated patients, the erythroid response rate was reported to range from 38% to 72% according to the 2000 International Working Group (IWG) criteria, while the response duration was noted to range from 12 months to more than 51 months [29]. Notably, in an epoetin extension study, the median response durations for epoetin alone and for epoetin plus granulocyte colony-stimulating factor were reported to be 34 months and >20 months, respectively [9].

Overall, meta-analyses and systematic reviews have revealed no significant differences in pooled response rates for epoetin alfa and darbepoetin alfa and they have indicated clinical benefits of ESAs, with benefits observed across key clinical outcomes (improved erythroid response rates and duration of response), as well as reduction in transfusion needs [1,30,31,32].

Our previous study involving the interim analysis of 12-month results indicated the similar efficacy of epoetin alfa and darbepoetin alfa among low-risk and intermediate-1-risk MDS patients with no differences in treatment responses between the treatment groups (12-month response rates: 58.1% for epoetin alfa and 41.9% for darbepoetin alfa), whereas the likelihood of earlier treatment response (within the first 3 months: 62.7%) and achievement of an earlier reduction in transfusion needs was noted in the epoetin alfa group [12]. In the current extension study, while the two treatment groups had similar efficacy in terms of rates and durations of treatment responses for up to 48 months of follow-up, the epoetin-treated patients had a slower decrease in treatment response from baseline along with significantly higher hemoglobin levels accompanied by a greater reduction in transfusion needs from 24 to 48 months of follow-up.

In a meta-analysis of 55 studies, transfusion independence was concluded to be associated with decreased mortality (hazard ratio: 0.41; 95% confidence interval: 0.29-0.56) [33]. Hence, the increased likelihood of transfusion independency with long-term epoetin treatment and lower-risk MDS in our cohort seems to be particularly notable given that the primary target in managing patients with lower-risk MDS in daily practice is to achieve transfusion independence, which is associated with improved survival [6,15,20,33,34,35]. Indeed, epoetin alfa treatment for patients with MDS is considered likely to achieve durable responses, thereby guaranteeing an improvement in the quality of life for these patients [10].

In a retrospective cohort study of 36 patients diagnosed with MDS and treated with epoetin alfa (30,000 to 60,000 IU per week), the authors reported a response rate of 80.5% with surprisingly prolonged responses (range: 25-175 months) in 82.8% of patients, who were also transfusion-independent and had favorable response stratifications [10]. Hemoglobin values were reported to increase significantly after 24 months and up to 175 months after the initiation of epoetin alfa treatment, and they remained above the baseline values, while the overall survival rate was 51.64% after a median of 65 months of treatment along with 43.5-month median event-free survival [10]. The authors indicated an association of epoetin alfa with higher overall survival and event-free survival rates and longer response durations in their study than previously described in the literature, and they emphasized that the likelihood of sustained rates of erythroid response following the initiation of epoetin alfa treatment also reflected the need for prolonged treatment to obtain the full clinical benefits [10].

The factors associated with treatment response in ESA-treated MDS patients have been reported to include certain clinical characteristics such as low serum EPO levels, a lack of transfusion dependence, and a low-risk stratification based on the Revised International Prognostic Scoring System [5,29,32,36]. In particular, high-risk stratifications and transfusion dependence, in relation to their negative impact on event-free survival, are considered likely to be predictors of poor response to epoetin alfa treatment [10]. The association of epoetin alfa versus darbepoetin alfa treatment as well as low-risk versus intermediate-1-risk status with significantly higher hemoglobin levels and greater decrease in transfusion dependency in the current study supports the previously reported data on lower rates and shorter durations of response to epoetin treatment in high-risk MDS patients and those with transfusion dependence [10,37]. Indeed, treatment with ESAs has been associated with delays in transfusion needs along with substantial increases in hemoglobin levels for longer periods of time [10]. The increased likelihood of erythroid response with a longer duration of ESA treatment among later responders has also been suggested together with the potential benefit of continuing ESA administration even after a lack of treatment response within the initial 8 to 12 weeks [7,36,38].

The dose-dependency of ESA efficacy has also been emphasized with the consideration of epoetin at 60,000 U/week and darbepoetin at 300 µg/week as being superior to lower doses [11,35,39], while more frequent dosing and prolonged treatment are considered to be necessary to obtain the full clinical benefit [29,35,38]. In addition, the implementation of the stringent 2006 IWG criteria (1.5 g/dL hemoglobin increase maintained for 8 weeks, even in patients with low transfusion burdens) is considered likely to yield a lower-than-expected clinical benefit rate [35]. An increase in the observed response rates with ESAs was reported after relaxing the strict interpretation of the 2006 IWG criteria, with these rates shifting from 15% to 24% in the ARCADE study and from 32% to 46% in EPOANE3021 [1,18,35], as well as in other ESA studies using other erythroid response criteria [1,40,41]. Moreover, early dose reduction for patients with a rapid hemoglobin rise who are still anemic is suggested to hamper the achievement of sustained hemoglobin responses and thus to lower the erythroid response rate [1]. Nonetheless, the recently proposed revised IWG criteria for assessment of hematologic response include the requirement that the duration of hematologic improvement last 16 weeks (versus 8 weeks), among other recommendations [11,42].

Importantly, given the occurrence of functional changes in hormonal receptors upon chronic exposure to agonists and that ESAs are used for the long-term treatment of anemia, gradual decreases in responses to ESAs after 24 months could also be a result of the downregulation of EPO receptors after prolonged exposure to ESAs or may be related to disease progression [43,44,45].

Study Limitations

Certain limitations to this study should be considered. First, due to the retrospective design, establishing temporality between cause and effect is not possible. Second, the lack of data on the timing of ESA initiation and the use of patient-reported outcome measures related to quality of life are other limitations. Further data on these points would extend the knowledge achieved in the current study.

Conclusion

This real-life long-term ESA extension study investigated the clinical efficacy of epoetin alfa and darbepoetin alfa for up to 48 months and revealed that treatment efficacy reached a plateau starting from the 24th month of therapy with a continuing decrease in treatment response rates regardless of treatment type, risk status, or gender. Nonetheless, significantly higher hemoglobin levels and marked improvement in transfusion needs were noted among epoetin-treated patients compared to darbepoetin-treated patients and in the low-risk group compared to the intermediate-1-risk group. These findings emphasize the likelihood of long-term epoetin treatment achieving a durable reduction in transfusion needs and a substantial increase in hemoglobin levels for longer periods by delaying the need for transfusions and thus increasing the probability of improved quality of life and prolonged survival for low-risk MDS patients.

Footnotes

Ethics

Ethics Committee Approval: This study was approved by the Zonguldak Bülent Ecevit University Clinical Research Ethics Committee (date of approval: 01/12/2021; reference number/protocol no: 2021/23).

Informed Consent: Written informed consent was obtained from all patients.

Authorship Contributions

Concept: M.A.A., Ş.E.; Data Collection or Processing: M.A.A., A.G., İ.H.A., C.S.; Analysis or Interpretation: M.G.P., İ.H.A., C.S.; Literature Search: M.A.A., A.G., İ.H.A., M.G.P., C.S., T.H.; Writing: Ş.E., A.Z.B., B.G.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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