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The Oncologist, Vol. 12, No. 10, 1264-1273, October 2007; doi:10.1634/theoncologist.12-10-1264
© 2007 AlphaMed Press

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 Efficacy and Safety of Erythropoiesis-Stimulating Proteins in Myelodysplast...
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Symptom Management and Supportive Care

Efficacy and Safety of Erythropoiesis-Stimulating Proteins in Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis

Susan D. Rossa, I. Elaine Allenb, Corey A. Probsta, Brian Sercusa, Sheila M. Creana, Gayatri Ranganathana

aUnited BioSource Corporation, Medford, Massachusetts, USA; bBabson College, Wellesley, Massachusetts, USA

Key Words. Anemia • Myelodysplasia • Meta-analysis • Epoetin • Darbepoetin

Correspondence: Susan D. Ross, M.D., F.R.C.P.C., United BioSource Corporation, 101 Station Landing, Medford, Massachusetts 02155, USA. Telephone: 781-395-0700; Fax: 781-395-7336; e-mail: Susan.ross{at}unitedbiosource.com; Web: http://www.unitedbiosource.com

Received April 5, 2007; accepted for publication July 17, 2007.

Disclosure: S.D.R., C.A.P., S.M.C., B.S., and G.R. are employees of United BioSource Corporation (UBC) performing contract work for Amgen. I.E.A. received financial compensation from UBC for statistical consulting and reviewing the manuscript. No potential conflicts of interest were reported by the planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Provide the current best estimates of hemoglobin response with erythropoiesis-stimulating proteins in anemia of MDS.
  2. Specify prognostic factors for response that are potentially useful.
  3. Describe the gaps in the existing evidence base regarding these agents in MDS.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
 References
 
Objective. The objective was to assess the efficacy and safety of erythropoiesis-stimulating proteins (ESPs) in anemia of myelodysplastic syndrome (MDS).

Method. A systematic review and meta-analysis was conducted covering English-language studies published from 1980 to December 2005.

Results. Fifty-nine studies qualified: five controlled trials (n = 354), all epoetin versus control (EvC); 51 epoetin single-arm studies (n = 1,650); and three darbepoetin single-arm studies (n = 102). In the EvC studies, epoetin patients demonstrated a significant advantage over controls in terms of hemoglobin (Hb) response (odds ratio, 5.2; 95% confidence interval, 2.5–10.8). Hb response was 48.1% in single-arm darbepoetin studies, 32.1% in epoetin single-arm studies, and 27.3% in EvC studies. Major Hb response averaged 38.8% in darbepoetin studies, 24.5% in epoetin single-arm studies, and 11.4% in EvC studies. Stratified analyses suggest that lower baseline erythropoietin levels, longer treatment durations, and concurrent iron may be associated with greater Hb response to ESPs. None of the analyzable predictors of Hb response (gender, baseline Hb, ESP type, and ESP duration) were significant in meta-regression analyses. In the few studies with quality-of-life measures, ESP groups attained a pre–post change (Functional Assessment of Cancer Therapy – Fatigue) that exceeded minimum clinically important differences. Selected adverse event rates did not differ between the epoetin and darbepoetin groups.

Conclusion. Published studies suggest that ESPs are efficacious in anemia of MDS. Hb response appears higher in darbepoetin patients than in epoetin patients, and safety appears comparable, but darbepoetin data are sparse, and there are as yet no direct comparison studies.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
 References
 
Myelodysplastic syndromes (MDSs) are a group of disorders characterized by one or more peripheral blood cytopenias secondary to bone marrow dysfunction [1]. The incidence and prevalence of MDSs are difficult to determine, in part because of changing definitions of MDS over the years, the lack of consistent tracking systems, and the fact that, as general populations are aging, MDS incidence may also be changing. In Europe, new cases of MDS have been estimated at 3–20 per year per 100,000 (higher in older age groups) [2]. In the U.S., the American Cancer Society estimates 7,000–12,000 new cases per year [3].

Treatment choices for MDS are varied and include cyclosporine, thalidomide and its derivatives, tumor necrosis-factor inhibitors, cytarabine, and 5-azacytidine, of which only the latter has U.S. Food and Drug Administration approval for this indication. Bone marrow transplantation is the best hope for cure, but it is not appropriate for many patients. While the ultimate goal of treatment is to extend survival, treatment is also intended to prevent the leukemic progression that occurs in up to 30% of patients. The more immediate treatment goals are to control symptoms and improve quality of life (QoL), while minimizing side effects of therapy.

Anemia is a major contributor to the symptomatology of MDS, because it is associated with fatigue, weakness, and shortness of breath. These effects of anemia may be temporarily ameliorated by RBC transfusions. Erythropoiesis-stimulating proteins (ESPs) have also been tested and used in anemic MDS patients. This is an off-label use, however, as ESPs (e.g., epoetin alfa and beta, and darbepoetin) have not yet been approved by regulatory authorities for use in MDS. The ability of patients with diseased bone marrow to respond to ESPs has been questioned, and concerns regarding safety, especially the potentiation of leukemic progression by an exogenous growth factor, have been raised as possible objections to using ESPs in MDS. Unfortunately, the only treatment alternative—repeated transfusions—has safety concerns of its own [4].

Therefore, the purpose of this review was to assess what is currently known about the efficacy and safety of ESPs in anemia of MDS by performing a systematic review of the literature.


   METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Acknowledgments
 References
 
In general, the methods used for this review followed current best practices for conducting systematic reviews and meta-analyses of the literature [5, 6].

Studies
The literature search had both electronic and manual components. MEDLINE (via PubMed) was searched using the following search strategy:

  1. EPO OR epoetin OR erythropoietin [MeSH] OR procrit OR epogen OR darbepoetin OR DARB OR ARANESP OR NESP or Neorecormon.
  2. Myelodysplastic syndromes [MeSH] OR MDS OR myelodysplasia.
  3. #1 AND #2.

Limits: Publication date 1980–2005, English, and human, NOT case reports, letters, news, editorials, reviews.

In addition, two strategies were used to identify recently published papers not yet indexed in MEDLINE: (a) the PubMed search included a key word search for the past 6 months with no limits; and (b) Current Contents® was searched for the past 6 months, using similar search terms. In addition, the Cochrane Library was searched for any recent systematic reviews to serve as a source of further references. A manual check of the reference lists of all accepted papers and of recent reviews was performed to supplement the above electronic searches. Very recent studies, available only as abstracts from recent (2003–2005) annual meetings of the American Society of Clinical Oncology, European Society for Medical Oncology, and American Society of Hematology were accepted if they otherwise met eligibility criteria for this review. The search cutoff date was December 15, 2005.

All English-language prospective interventional study designs with at least 10 adults with primary MDS receiving an ESP for anemia or retrospective observational studies of at least 300 ESP patients were accepted. Any antineoplastic treatment except stem cell transplant was acceptable. Studies had to report at least one of the following outcomes of interest: hemoglobin (Hb) change, RBC transfusions, number of patients with Hb response, and QoL using validated instruments: the Functional Assessment of Cancer Therapy – Fatigue (FACT-F) or Linear Analogue Self-Assessment (LASA) equivalents, as pre–post or change scores. Selected adverse events (AEs) were also sought: deaths, patients progressing to acute myelogenous leukemia (AML), venous thromboembolism (VTE), hypertension (new or worse), red cell aplasia, thrombocytopenia, leukopenia, and renal dysfunction (new or worse). In cases where multiple reports of the same study were published (kin studies), those with the most recent and complete data were used to avoid double counting.

Data elements of interest were extracted to data forms by one investigator and reviewed for agreement by a second. Data discrepancies were resolved by consensus of the two investigators prior to entry into a relational database. All data entries were verified back to the extraction forms prior to locking the database for analysis.

Randomized controlled trials (RCTs) were also critically appraised at the time of data extraction using the Jadad scale [7]. Each accepted RCT was scored for features of randomization method used, blinding of treatments, and accounting for all patients entered and withdrawn.

Statistical Analyses
Study-, patient-, and treatment-level data were summarized using basic descriptive statistics (simple counts and means). The number of patients randomized or enrolled was used in the calculation of study and patient demographics. The main objective of the analyses was to quantify and compare the efficacy and safety outcomes of controlled trials of ESPs versus standard care (transfusions) for managing anemia in MDS patients. The efficacy of the different ESPs in noncontrolled investigational and real-world settings was also of interest. Outcomes of interest included: Hb response (however defined), as well as major and minor response (per International Working Group [IWG] criteria), transfusions, and QoL changes on FACT-F [8] and LASA scales. The percentage of patients with each of the selected AEs listed above was computed for each treatment group, and risks in ESP patients relative to control groups were computed as data permitted.

Efficacy and safety outcomes of interest were first synthesized via weighted means for all studies with a given outcome so as to provide a non–meta-analytic estimate for each result. A drawback of the weighted means is that they ignore between-study variation, for example, give results similar to those found through a fixed-effects meta-analysis [9, 10]. Efficacy and safety outcomes were thus also synthesized by meta-analytic pooling of like-treatment group results across studies using the random effects model (REM) [11] for each estimate. The REM is a more conservative methodology for combining results across studies, taking into consideration both within- and between-study variation.

For studies where binary outcomes (e.g., responders) were meta-analyzed, results are expressed as odds ratios (ORs) with 95% confidence intervals (CIs) for active versus control treatments. In such cases, an OR <1 indicates a lower risk for active than for control treatment, and an OR >1 indicates a greater risk for active than for control treatment. For studies where continuous outcomes (e.g., Hb change) were meta-analyzed, results are expressed as mean differences with 95% CIs. QoL scores were interpreted using the concept of minimal clinically important difference (MCID). The MCID is the smallest difference in score that patients perceive as beneficial. For the FACT-F subscale, the MCID is 3.0 points [12, 13].

Sensitivity analyses also included meta-regressions to test the impact of several study-, patient-, and treatment-level covariates upon the main efficacy outcome, Hb response. There were few covariates of interest that had comprehensive and well-distributed results available across trials. These were: gender, baseline Hb, ESP type (epoetin or darbepoetin), and ESP duration (≤12, > 12–20, >20 weeks). Other covariates, such as the International Prognostic Scoring System risk category [14] or iron use were of interest, but insufficiently reported to use in the meta-regression analyses of predictors.

In the extraction of safety data, a zero was extracted only when there was a statement to the effect that a particular event did not occur. No assumptions were made from the absence of data, that is, a zero was not assumed when no mention was made, but rather, data were treated as missing, and not included in analyses.

Study heterogeneity was assessed using both Cochran's Q [15] and the I2 statistic [16]. All calculations were performed using SAS software version 9.1 (SAS Institute, Inc., Cary NC), SPSS software version 14.2 (SPSS, Inc., Chicago, IL), and Comprehensive Meta-Analysis version 2.0 (Biostat, Inc., Englewood, NJ).


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Acknowledgments
 References
 
Fifty-nine primary studies (n= 2,106) were eligible for inclusion in this review. The 59 primary studies were associated with a total of 14 kin studies, that is, additional publications about the same study. There were 36 studies published in 1990–1999 and 23 published in 2000 or later. All the darbepoetin studies were in or after 2000. Fifty-three studies were full papers, and six were available only as meeting abstracts. Forty-five studies were in Europe, while 12 were in North America. The remaining two were in Japan. Industry sponsorship was identified in 30 studies.

There were only five controlled trials: four RCTs [17–20] and one non-RCT [21]. All controlled trials were epoetin versus control (EvC) designs (n = 354). There were no darbepoetin versus control studies, nor any epoetin versus darbepoetin studies. The majority of the studies (54) were uncontrolled case series (UCSs) (n = 1,752, of which 1,650 were epoetin and 102 darbepoetin).

Study durations (available in 40 studies) were in the range of 1–104 weeks, averaging 18.0 weeks. Extractable (and analyzable) Hb response outcomes were available in four EvC studies (the fifth [21] only reported Hb responders in the epoetin group, not in the control group), 46 epoetin UCSs, and three darbepoetin reports. Further delineation of major and minor Hb response was available in only 32 studies. Hb change results, transfusion outcomes, and analyzable QoL (FACT-F or LASA) change scores were available in fewer studies. AEs of interest were reported in 53 studies: all five EvC studies, and 45 epoetin and all three darbepoetin UCSs.

Overall, men outnumbered women (56% versus 44%), and the average age was 70 years (range, 57–88), with an average baseline Hb level of 8.4 g/dl (range, 6.0–10.1) and baseline serum erythropoietin level of 374 u/l (range, 44–2,466). ESP efficacy and safety outcomes were rarely reported by baseline risk category. The percentage of marrow blasts at baseline was reported in only 14 studies (all epoetin UCSs), and averaged 5.4% (range, 2.0%–18.8%). No substantive differences among ESP types were noted for these baseline characteristics.

The distribution of groups and patients by ESP type, dosing route, frequency, and duration is shown in Table 1. Most authors reported dose reduction rules in the event of exceeding the target Hb or in the event of toxicity. Target Hb when reported (12 studies) was in the range of 8–13 g/dl, and the Hb level at which ESP should be discontinued was reported in seven studies (range, 12–13 g/dl in five studies and no change or 50% change from baseline in two studies).


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  		Table 1. Anemia treatment characteristics: ESP treatment groups

 
In 39 of the 56 epoetin studies, no concurrent chemotherapy was administered to patients (n = 1,438). Thalidomide was used in two epoetin studies, other miscellaneous agents (e.g., steroids or hormones) were administered in seven studies, and seven did not report any concurrent treatment for MDS. Of the three darbepoetin studies, in two it was determined that no MDS treatment was given, and in one, concurrent MDS treatments were not reported.

Concomitant G-CSF or GM-CSF was used in 16 epoetin groups (n = 457) and only one darbepoetin group (n = 12). Concurrent iron (as an oral supplement in all cases but one) was identified in only seven epoetin studies (n = 273) and no darbepoetin studies. The remaining studies were silent on the use of iron.

Efficacy of ESPs in MDS
The primary outcome of interest was the percentage of patients with Hb response. Definitions of responders were relatively consistent from study to study, with most authors using the IWG criteria (or minor modifications thereof) [22], defining a major Hb response as an increase in Hb from baseline of at least 2 g/dl and a 100% reduction in transfusion requirements and a minor Hb response as an increase in Hb of 1–2 g/dl from baseline and at least a 50% reduction in transfusions. Hb overall response is the sum of the major and minor responders.

In only four EvC studies [17–20] was this outcome available and analyzable, because the fifth EvC study [21], a nonrandomized controlled trial, did not report the Hb response for control patients. The Hb response rate in the epoetin groups in these four EvC studies was 27.3%, and in control groups it was 6.7% (Table 2). The OR for Hb response was 5.2 (95% CI, 2.5–10.8), significantly in favor of epoetin (p < .01). There was no significant heterogeneity among these EvC trials. The advantage for epoetin was evident across all EvC studies and reached statistical significance in three of the four studies (Fig. 1).


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  		Table 2. Anemia response in MDS studies

 


Figure 1
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  		Figure 1. Epoetin versus control: hemoglobin responders.

Abbreviations: CI, confidence interval.

 
Three of the four studies with this outcome were of short duration (≤12 weeks), and none used any concurrent antineoplastic treatment. Three used concurrent G-CSF or GM-CSF (Hb response OR, 4.6; 95% CI, 2.2–9.9), and one used concurrent oral iron (Hb response OR, 4.6; 95% CI, 1.4–15.2). In only one was the baseline serum erythropoietin level (<500 U/l) reported (Hb response OR, 29.5; 95% CI, 1.9–531.2).

In three of the EvC studies, epoetin was administered s.c., in two studies the dosing frequency was three times per week, and it was every day in the remaining two studies; dosing duration was ≤12 weeks in three of the four studies. The OR for Hb response in studies in these strata did not differ much from the overall result.

Efficacy outcomes for the epoetin single-arm studies are also displayed in Table 2. In all epoetin groups in these studies, the total Hb response rate was 32.1% (95% CI, 26.3%–37.9%), with an average major response rate of 24.5% (95% CI, 16.1%–33.0%) and a minor response rate of 17.8% (95% CI, 10.1%–25.5%). (Note: The major and minor response rates do not equal the total response rate here because of different studies contributing to each estimate.) Hb increased from baseline, on average, by 10.2% (95% CI, 4.7%–15.7%) in these groups.

Stratified analyses of these studies suggest that groups of patients with a higher average baseline serum erythropoietin level (≥500 u/l) have a smaller Hb change (a 0.3- versus 1.2-g/dl increase) and a lower rate of Hb response (27.3%) than groups with a lower baseline serum erythropoietin level (34.9%). Studies with a longer duration (>20 weeks) of epoetin use had a higher Hb response rate (40.2%) than studies with a shorter duration (≤12 weeks) of epoetin use (30.8%). There also appears to be a higher rate of major Hb response in the longest duration studies (34.2%) than in the shortest duration studies (19.9%). The use of concomitant G-CSF showed little difference in efficacy outcomes (e.g., 38.3% Hb response) compared with overall results (32.1%). However, any identified use of iron was associated with a greater Hb change (1.7 g/dl, or a 19.5% increase), a lower percentage of patients transfused (33.3%), and a higher percentage of patients with Hb response (50.0%), relative to the overall results for single-arm studies (0.8 g/dl, 10.2% Hb increase, 62.4% transfused, and 32.1% Hb response, respectively).

For the three darbepoetin single-arm studies [23–25], efficacy results are displayed in Table 2. The average Hb response rate was 48.1% (95% CI, 25.2%–70.9%). The average major Hb response rate was 38.8% (95% CI, 30.5%–47.1%) and the average minor Hb response rate was 9.2% (95% CI, 0%–25.2%). There were too few studies for meaningful stratified analyses in any category except for study duration. The study with the longest duration (>20 weeks) of darbepoetin use [25] had a higher Hb response rate (55.8%) than the study [24] with the shortest duration (12 weeks) of darbepoetin use (40.0%). None of the darbepoetin studies reported use of concomitant iron.

Lastly, Figure 2 summarizes the meta-analyzed results for Hb response outcomes for each type of treatment. It appears that darbepoetin has superior results, but the 95% CIs overlap with those of epoetin. The duration of response and relapse rates were not efficacy outcomes for this analysis, and were rarely reported, because most studies did not provide long-term follow-up information. Casadevall et al. [17] reported that six of eight patients who continued epoetin past the initial 12-week study period relapsed, but they did not report time to relapse. Stasi et al. [26] reported a median time to relapse of 20 weeks. Three additional studies [23, 27, 28] reported mean or median durations of response—with continued administration of the ESP—in responders of 54 weeks, 12.5 months (major responses only), and 7.5 months, respectively.


Figure 2
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  		Figure 2. Meta-analyses of hemoglobin (Hb) response rates: all treatment arms.

Abbreviations: CI, confidence interval; RCT, randomized controlled trial; Tx, treatment; UCS, uncontrolled case series.

 
QoL changes on FACT or LASA scales were infrequently and inconsistently reported, and thus were not meta-analyzable. The Spiriti et al. [29] study evaluated Hb response and changes in FACT – Anemia (FACT-An) scores (including the fatigue subscale) in 133 low-risk MDS patients with baseline Hb levels ≤10 g/dl. Patients received loading doses of 40,000 units of epoetin twice weekly, followed by once-weekly maintenance dosing. Change scores for the 86 patients evaluated at 8 weeks exceeded the MCID for both the FACT-An (+7.0) and FACT-F (+3.0), at 8.8 and 7.0 points, respectively. The authors were further able to show that improvement in Hb level was significantly and positively correlated with improved QoL. These epoetin findings were supported by the Stasi et al. [25] study of weekly darbepoetin in 53 low–intermediate risk patients with Hb levels <10 g/dl. That study reported a FACT-F score change at 6 months of +4.0, as well as a LASA overall (0–100) score change of +5.0. LASA changes in each domain assessed (energy, daily activities, and overall) were statistically significant improvements, with significant positive correlations to change in Hb. This was also true for the FACT-An fatigue and anemia subscales in Hb responders. Conversely, the Casadevall et al. [17] study of epoetin, 20,000 units, plus G-CSF three times a week versus standard care in 60 low-risk MDS patients with baseline Hb levels ≤10 g/dl did not support these findings. The Casadevall et al. [17] study reported no significant differences in pre–post scores within groups or between groups (in 23 and 24 evaluated patients, respectively, at 12 weeks) in either the FACT-An total or fatigue subscale scores. They also provided results for patients completing the questionnaires at later time points (weeks 28 and 52), but patient attrition at these later time points increased, and although differences between the groups were greater, these differences never reached statistical significance.

Meta-regression analyses for predictors of Hb response were run using all the treatment arms separately (but with a factor for type of study). None of the following covariates were significant: baseline Hb, percentage male, size of study, or ESP duration. The factor for treatment (control, epoetin, darbepoetin) was significant for control compared with either epoetin or darbepoetin, and there was no significant difference between epoetin and darbepoetin.

Multivariate analyses of predictors of response were reported in six studies [24, 25, 29–32]. The most frequently reported significant predictor was baseline serum erythropoietin level, with low levels predicting response to exogenous ESPs ([24, 25, 31, 32]. Low pretrial transfusion needs were also predictive of ESP response, in three studies [24, 31, 32].

In a further seven studies [19, 33–38]), analyses of Hb response were stratified according to baseline erythropoietin levels. In four of these studies, a high or low baseline serum erythropoietin level was not associated with a significant difference in the Hb response rate. However, in the three remaining studies, this stratification was associated with a difference in the Hb response rate [19, 33, 37].

Safety of ESPs in MDS
Table 3 shows frequencies of selected AEs by ESP type, as well as the OR for these AEs when reported in EvC studies. The safety data available for the darbepoetin studies are very sparse. For the epoetin studies, they are more robust. In these studies, event rates for all AEs captured were <10% in all instances except for thrombocytopenia in a single epoetin group in an EvC study [18]. None of the ORs reached statistical significance.


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  		Table 3. Safety of ESPs in MDS

 
We note that progression to AML (not typically defined in these studies) was captured only for the formal study period. In EvC studies, 0.9% of epoetin patients and 8.2% of control patients progressed to AML. The OR is not significant, presumably because of the low numbers of patients and events. In epoetin and darbepoetin single-arm studies, the AML frequencies were 4.4% and 1.1%, respectively. In five studies [17, 21, 39–41], long-term follow-up (up to 44 weeks) regarding AML incidence was also available. Differences in AML incidence are difficult to interpret because of between-study differences in patient mix regarding MDS risk category, on-study and poststudy treatment exposures, monitoring activities, and follow-up times.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Acknowledgments
 References
 
This systematic review of ESPs in the treatment of anemia of MDS demonstrates significant efficacy of epoetin versus standard care or placebo controls in terms of Hb response (OR, 5.2; 95% CI, 2.5–10.8), the primary efficacy outcome in most of the studies reviewed. While there were no controlled trials of darbepoetin yet reported, at least one is currently under way [42]. The single-arm studies of darbepoetin reported an Hb response frequency (48.1%) that was similar or superior to those observed in the epoetin studies (32.1% in epoetin single-arm studies and 27.3% in EvC studies). The major Hb response rate averaged 38.8% in darbepoetin studies, also higher than in the epoetin single-arm studies (24.5%) and EvC studies (11.4%). These observations are in contrast to the Hb response rates recently reported in another systematic review [43], wherein epoetin groups achieved an Hb response rate of 57.6%, versus 59.4% for darbepoetin. This difference in findings is likely explained by different study eligibility criteria for each review, and until those details become available, interpretation remains difficult. It is safe to conclude, however, that head-to-head studies of these agents are needed.

The evidence to date further suggests that a lower baseline erythropoietin level may be associated with a higher Hb response rate to ESPs. This is plausible because refractory anemia in the face of a high endogenous erythropoietin level may indicate relative nonresponsiveness of bone marrow. Conversely, anemia associated with a low serum erythropoietin level may respond more readily to exogenous ESPs. These observations are further supported by the findings of other more recent ESP studies [44–46] reported since our search cutoff date of December 2005, wherein a lower serum erythropoietin level was associated with a greater Hb response rate to ESPs. These post hoc observations should now be studied prospectively to determine if serum erythropoietin level could serve as a reliable guide to selection of MDS patients for ESP treatment.

The results of this systematic review also suggest that ESP treatment for a longer duration and the use of concurrent iron may be associated with a higher frequency of Hb response. These possible ways to enhance efficacy of ESPs in MDS require further study, as do extended dose regimens that may enhance convenience, adherence, and efficacy of long-term regimens.

As for the other efficacy outcomes of interest (absolute change or percentage change in Hb from baseline, and percentage of patients transfused), an ESP advantage over controls is suggested, but the available evidence is less compelling than for Hb response outcomes. In the few studies measuring QoL using similar validated instruments, however, it is suggested that QoL improves in ESP-treated patients, and this improvement is of a magnitude that is clinically meaningful [17]. This finding was also recently reiterated in a different report of the new study noted above [47], and is further enhanced by the observation that patients with the greatest Hb increase had the greatest improvements in FACT-F.

As for the safety of ESPs, selected AEs were generally reported in <10% of treated patients, regardless of ESP type or study design. ESPs in combination with CSFs did not appear to be associated with higher rates of progression to AML, a concern that has been raised previously about coincident use of these agents [48]. Whether there are differences in safety among ESPs, and whether ESPs will be proven to be safe with the long-term use that may be needed in MDS, remain to be seen. Only comparative, long-term follow-up trials will resolve these questions.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Acknowledgments
 References
 
The studies in this review comprise the best available evidence on the efficacy and safety of ESPs in the treatment of anemia associated with MDS. Epoetin treatment provides a significant advantage in terms of Hb response. Although the evidence for darbepoetin is sparse, thus far it appears that darbepoetin is as effective as epoetin. Controlled trials of darbepoetin versus standard care or placebo controls are needed to establish not only the efficacy and safety, but also the costs and health care use associated with these treatment alternatives. Head-to-head trials of epoetin versus darbepoetin are also needed to compare Hb response in comparable patients using comparable response criteria, as well as QoL and other efficacy measures of potential interest, such as long-term survival, relapse rates, and AML progression.


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
References
 
The authors wish to thank Drs. Tamas Suto, Marco Schupp, and Bin Yao of Amgen (Europe) for their helpful advice. This research was funded by Amgen (Europe) GmbH.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
 References
 

  1. National Cancer Institute. Myelodysplastic Syndromes (PDQ®): Treatment. Available at http://www.cancer.gov/cancertopics/pdq/treatment/myelodysplastic/HealthProfessional. Accessed October 23, 2006.
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