Uses of Epoetin for Anemia in Oncology

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

Prepared by:
Blue Cross and Blue Shield Association
Technology Evaluation Center
Jerome Seidenfeld, Ph.D.
Principal Investigator

Naomi Aronson, Ph.D.
Margaret Piper, Ph.D., M.P.H.
Carole Redding Flamm, M.D., M.P.H.
Vic Hasselblad, Ph.D.
Kathleen M. Ziegler, Pharm.D.
Investigators

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John M. Eisenberg, M.D.	Douglas B. Kamerow, M.D.
Director	Director, Center for Practice and
Agency for Healthcare Research and Quality	Technology Assessment
	Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.

Anemia is relatively common in patients with either hematologic or solid tissue malignancies. When cancer treatment or the disease itself decreases production of or impairs response to endogenous erythropoietin, epoetin treatment may correct the resulting anemia. This systematic review compares outcomes of managing anemia with epoetin (and red blood cell [RBC] transfusion used as necessary) with using RBC transfusion alone. Four groups of patients with malignancy are included: (1) patients with anemia or at risk of anemia resulting primarily from cancer therapy; (2) patients with anemia resulting primarily from their malignant disease and who may also be receiving cancer therapy; and patients who are anemic as a result of bone marrow ablation prior to (3) allogeneic or (4) autologous stem-cell transplantation.

The MEDLINE, CancerLit, and EMBASE databases were searched from 1985 through 1998 and Current Contents on Diskette and Medscape Oncology through October 1999 for the terms: erythropoietin (Medical Subject Heading [MeSH]); epoetin alfa (MeSH); erythropoietin (tw); epoetin (tw); Epogen (tw); Procrit (tw); Eprex (tw); Marogen (tw); Recormon (tw); epo (tw); Anemia/drug therapy (MeSH; included all subheadings); Anemia/therapy (MeSH; included all subheadings); Anemia/diet therapy (MeSH; included all subheadings). The search was then limited to "neoplasms" or "myelodysplastic syndromes" and studies on human subjects. The yield was 2,943 references.

This systematic review is limited to controlled trials comparing the outcomes of managing anemia with and without the use of epoetin in one of the four patient populations of interest. Uncontrolled trials were excluded.

We used a prospectively designed protocol conducted by two independent reviewers, with disagreements resolved by consensus. The meta-analysis used a random effects model to combine data on odds of transfusion in patients with anemia due primarily to cancer therapy.

For patients with anemia resulting primarily from cancer therapy, epoetin reduces the odds of transfusion. The overall number needed to treat (NNT) is 4.4 (95 percent confidence interval [CI], 3.6 to 6.1), which suggests four to five patients must be treated to spare one patient from transfusion. Sensitivity analysis found a smaller magnitude of risk reduction for double-blinded compared with unblinded studies. A large, double-blinded randomized trial, not yet published, found improvement in quality-of-life scores with epoetin. Assessment of the study methodology and clinical significance of the findings awaits publication of the full report. The most robust evidence that epoetin improves outcomes is from trials in patient groups with baseline hemoglobin (Hb) at or below 10 g/dL. The evidence is not adequate to determine whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds.

As many as one-half of all patients did not achieve a hematologic response to epoetin. Thus, nonresponding patients may account for much of the transfusion use in the epoetin arms of these trials. To achieve the most efficient use of epoetin, more systematic evidence is needed on patient characteristics that predict responsiveness and on early indicators of response.

Anemia primarily a result of malignancy included patients with multiple myeloma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and myelodysplastic syndromes. Epoetin increases Hb levels and achieves statistically significant hematologic response rates in these patients. The evidence on transfusion outcomes is sparse but suggests a favorable effect of epoetin. Hematologic response rates appear to be lower for patients with myelodysplastic syndrome; higher doses of epoetin may be necessary to achieve response.

For patients undergoing allogeneic stem-cell transplantation, epoetin decreased time to RBC engraftment by 1 to 2 weeks and may decrease the number of RBC units transfused. No reduction in length of hospitalization was reported. The evidence does not support a beneficial effect of epoetin for patients undergoing autologous stem-cell transplantation.

For patients undergoing cancer therapy, evidence demonstrates that epoetin reduces transfusion if treatment is initiated when declining Hb levels near 10 g/dL. Randomized controlled trials, adequately powered, are needed to determine whether initiating treatment at higher baseline Hb levels yields additional benefits in reducing transfusion use or improving quality of life.

This review identified common deficiencies in the design and reporting of trials on epoetin. Some methodologic deficiencies may result in overestimation of the effects of epoetin and inadequacy of reporting may limit the ability to interpret and generalize results. Future trials should maintain a higher standard of methodologic quality and completeness of reporting.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Seidenfeld J, Aronson N, Piper M, et al. Uses of Epoetin for Anemia in Oncology. Evidence Report/Technology Assessment No. 30. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center under Contract No. 290-97-0015.) AHRQ Publication No. 01-E009. Rockville, MD: Agency for Healthcare Research and Quality. June 2001.

Erythropoietin is an endogenous hormone, produced primarily in the kidney, which participates in regulating production of red blood cells (erythropoiesis). "Epoetin" is the term used for recombinant human erythropoietin. It was developed in the 1980s as a treatment for anemia. Epoetin replicates the biologic activity of the endogenous hormone and increases the number of red blood cells and thus the blood concentration of hemoglobin when given to persons with functioning erythropoiesis. The initial clinical use of epoetin was to treat patients with anemia of chronic renal failure, especially patients on dialysis (i.e., end-stage renal disease).

Anemia is a deficiency in the concentration of hemoglobin-containing red blood cells that occurs when the equilibrium between red cell loss and production is disturbed. Anemia is relatively common among patients with either hematologic or solid tissue malignancies. It may be caused by effects of treatment, the underlying disease, or both on production of or responses to erythropoietin (or it can be caused by other mechanisms). Anemia caused by occult bleeding, hemolysis, marrow replacement, or a nutritional deficiency is unlikely to respond to epoetin treatment but may be corrected using other therapies. When cancer treatment or the disease itself decreases production of or impairs response to endogenous erythropoietin, epoetin treatment may correct the resulting anemia. However, some individuals in whom other causes of anemia have been ruled out nonetheless fail to respond to epoetin.

The severity of anemia can range from mild to life threatening. The National Cancer Institute and Cooperative Oncology Groups use a grading system for anemia. Within normal limits (WNL) hemoglobin (Hb) values are 12.0-16.0 g/dL for women and 14.0-18.0 g/dL for men. There are four grades of anemia, indicating increasing severity: Grade 1, mild (10.0 to <WNL); Grade 2, moderate (8.0-10.0); Grade 3, serious/severe (6.5-7.9); Grade 4, life threatening (<6.5). A recent review cataloged the incidence and severity of anemia for various malignancies and treatment regimens, and found substantial variation. Because hematopoiesis is temporarily discontinued until after engraftment in patients undergoing myeloablation prior to transplant, nearly all would experience life-threatening anemia without RBC transfusion.

Data are unavailable to correlate the frequencies of anemia-related symptoms with Hb levels in cancer patients. However, the spectrum of symptoms associated with mild compared to severe anemia has been well described. Mild anemia is often asymptomatic or may manifest as tachycardia, palpitations, and dyspnea on exertion, and mild fatigue. Severe anemia is characterized by palpitations and dyspnea at rest, severe fatigue, and exercise intolerance. Other signs and symptoms include cardiac enlargement and impaired cognition.

RBC transfusion has long been the primary treatment of severe or life-threatening anemia. But transfusion is used cautiously in the treatment of moderate and mild anemia, because of the risks associated with exposure to allogeneic blood products and concern to conserve the blood supply. With the availability of epoetin, severe anemia may be prevented; however it is not useful for the acute treatment of severe or life-threatening anemia because adequate hematologic response does not occur until after 4 or more weeks of treatment. Epoetin is also used to treat or prevent mild anemia.

This evidence report/technology assessment was developed under contract by a team of reviewers/investigators from the Blue Cross and Blue Shield Association's Technology Evaluation Center (TEC).

This systematic review compares outcomes of managing anemia with and without the use of epoetin. Epoetin (with RBC transfusion used as necessary) was compared to RBC transfusion alone. Four groups of patients with malignancy are included in this systematic review.

Patients with anemia or at risk of anemia due primarily to cancer therapy. These are patients being treated for malignancy with chemotherapy, radiation, or chemotherapy and radiation.
Patients with anemia due primarily to their malignant disease and who may also be receiving cancer therapy. All patients in these studies had nonmyeloid hematologic malignancies or myelodysplastic syndrome.
Patients who are anemic as a result of bone marrow ablation prior to allogeneic stem-cell transplantation.
Patients who are anemic as a result of bone marrow ablation prior to autologous stem-cell transplantation.

This systematic review does not address use of epoetin to reduce the need for transfusion or to facilitate collection of autologous blood in patients undergoing surgery for cancer.

Outcomes of interest include preventing exposure to allogeneic blood (transfusion); reducing the number of RBC units transfused; improving symptoms of anemia (e.g., fatigue, dyspnea, sleeplessness, impaired concentration); reducing hospitalization; improving quality of life (measured by validated instruments); and incidence of adverse events (e.g., hypertension).

This systematic review also sought evidence on: the outcomes of epoetin in various patient populations (e.g., pediatric, geriatric); predictors of response to epoetin; and the effect of the characteristics of the administration of epoetin (e.g., dose, dosing regimen) on outcome. The team also sought to compare the costs of epoetin to transfusion alone, but no controlled trials reported such data. As a result, its review of evidence on cost is limited to a discussion of secondary cost analyses summarized in the introductory section of the full evidence report. What follows are the specific objectives and key questions for each of these patient groups.

For patients with anemia primarily of cancer therapy and patients with anemia primarily of malignant disease, the objective of this systematic review is to compare the outcomes of the following alternatives for managing anemia:

Initiating epoetin when the level of hemoglobin decreases to a specified threshold:
- Hb >12 g/dL
- Hb >10 and <12 g/dL
- Hb <10 g/dL or requiring blood transfusions.
Managing anemia without epoetin, using transfusion (usually initiated when hemoglobin decreases to a threshold between 7 and 9 g/dL).
Initiating prophylactic epoetin treatment concurrent with cancer therapy even if hemoglobin levels are above the anemic range. (Note that this alternative is not applicable to patients with anemia due primarily to malignancy, who are by definition already anemic and who may not be undergoing cancer therapy.)

For patients with anemia resulting from bone-marrow ablation prior to allogeneic or autologous stem-cell transplantation, the objective is to compare the outcomes of the following alternatives for managing anemia:

Managing anemia after bone-marrow ablation with transfusion initiated at a predefined Hb threshold (usually 7-10 g/dL) supplemented with epoetin treatment, beginning at the time of stem-cell infusion and continuing for a period of 4 to 8 weeks.
Managing anemia after bone-marrow ablation with transfusion initiated at a predefined Hb threshold.

The protocol for this review was prospectively designed to define: study objectives; search strategy; patient populations of interest; study selection criteria and methods for determining study eligibility; outcomes of interest; data elements to be abstracted and methods for abstraction; and methods for study quality assessment. Two independent reviewers completed each step in this protocol. Data was abstracted directly into two separate electronic databases and the databases were compared electronically. Disagreements were infrequent and generally resolved by consensus of the two reviewers; resolution by a third reviewer was seldom required.

A technical advisory group of six members provided ongoing guidance on all phases of this project. Four of the six technical advisors were appointed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), which each appointed two members to the technical advisory group.

A comprehensive literature search was performed that attempted to identify all publications of relevant controlled trials. The search process began with the MEDLINE, Cancerlit, and Embase databases. These online sources were searched for all articles published since 1985 that included at least one of the following text words (tw) or Medical Subject Headings (MeSH) terms in their titles, their abstracts, or their keyword lists: erythropoietin (MeSH); epoetin alfa (MeSH); erythropoietin (tw); epoetin (tw); Epogen (tw); Procrit (tw); Eprex (tw); Marogen (tw); Recormon (tw); epo (tw); Anemia/drug therapy (MeSH; included all subheadings); Anemia/therapy (MeSH; included all subheadings); Anemia/diet therapy (MeSH; included all subheadings).

The search results were then limited to include only those articles that were indexed under the MeSH terms "neoplasms" or "myelodysplastic syndromes" (including all subheadings), and that addressed studies on human subjects. The MEDLINE, Cancerlit, and Embase databases were last searched in December 1998; and total retrieval through this date was 2,915 references.

To supplement the above strategy, issues of Current Contents on Diskette and issues of Medscape Oncology, an electronic medical journal, were searched through October 30, 1999, to identify recently published articles that had not yet been indexed by the online databases. The team also searched abstracts presented at the 1999 meeting of the American Society of Clinical Oncology. An additional source of bibliographic information was provided by Ortho Biotech, Inc., the pharmaceutical company that markets epoetin for use in oncology patients. Finally, all relevant review articles, editorials, and letters published in 1995 or later were retrieved. Reference lists from these articles were searched for studies not identified by these methods. A total of 28 additional published reports were identified by supplementary searches for a total retrieval of 2,943 references considered for this review.

The primary study selection criterion required that studies be designed as controlled trials comparing the outcomes of managing anemia with and without the use of epoetin in one of the four patient populations of interest. Uncontrolled trials were excluded from this systematic review.

Abstraction of data on adverse events was also limited to controlled trials because the objective was to estimate the frequency of occurrence in the oncology setting of the common adverse effects of epoetin. This precluded analysis of uncontrolled series, because adverse events related to disease progression and cancer therapy could not be distinguished from those related to epoetin. Hypertension and thromboembolic events are known adverse effects of epoetin (but are generally manageable).

All controlled trials were published in English; no controlled trials published only in languages other than English were identified.

To supplement this systematic review, the team conducted a meta-analysis of the effect of epoetin on the odds of transfusion in patients with anemia or at risk of anemia due primarily to cancer therapy. A random effects model was used to combine results of the 14 randomized controlled trials that reported numbers of patients transfused. The odds ratio expresses the relative likelihood that epoetin-treated patients will be transfused compared to the likelihood for control patients.

Sensitivity analysis was performed to compare results of higher quality trials to lesser quality trials. A trial was classified as higher quality when it was randomized and double-blinded and met the team's criteria to limit subjects excluded from the analysis of results. It required that less than 10 percent of subjects within each study arm were excluded from the analysis, and that the ratio of exclusions between arms was less than a 2:1 ratio; or, alternatively, that results were reported as an intention to treat analysis.

This report has undergone extensive expert review. A preliminary analysis of the evidence base for this report was reviewed by the Blue Cross and Blue Shield Association Medical Advisory Panel, which includes nationally recognized experts in technology assessment and hematology/oncology. In addition, 20 external reviewers reviewed the study protocol and draft report, and revisions were made based on their comments. Eight reviewers were invited by the Technology Evaluation Center under the auspices of this task order for their expertise in medical oncology, hematology, transfusion medicine, quality of life, and systematic review methodology. One reviewer directs another AHRQ Evidence-based Practice Center and is a medical oncologist/hematologist. Ten of the external reviewers were appointed by professional organizations other than ASCO or ASH and by patient advocacy groups. These reviewers included clinical and research specialists involved in the treatment of cancer and/or management of cancer-related anemia and patient advocacy representatives. The final external reviewer was from the technical staff of Ortho Biotech, Inc., which markets epoetin alfa for the treatment of cancer patients.

The conclusions are based on data abstraction and analysis of 22 controlled trials with a total enrollment of 1,927 patients. All trials compared the outcomes of managing anemia with epoetin treatment or with RBC transfusion alone in patients undergoing therapy for a malignancy. Eighteen trials with a total 1,698 enrolled patients (88 percent) were randomized, and 7 randomized trials with a total of 853 patients were placebo-controlled and double-blind (44 percent). The number of patients reported as evaluable is 1,838, which is 95 percent of all enrolled patients. The team classified the 22 trials into 3 categories defined by the study patients' mean Hb at enrollment: Hb >12 g/dL; Hb >10 but <12 g/dL; and Hb <10g/dL. No trial directly compared the outcomes of initiating epoetin treatment at different Hb thresholds.

What are the relative effects on outcomes of managing anemia with epoetin compared to transfusion alone?What are the relative effects of epoetin treatment when different Hb thresholds are used to initiate treatment?
- The team found adequate and consistent evidence that epoetin increases Hb levels and percent of patients demonstrating hematologic response, when compared with controls managed by transfusion alone. This was true for pediatric patients as well as adults.
- For all randomized studies delivering epoetin subcutaneously, the odds of transfusion for epoetin-treated patients is reduced by a factor of 0.380 compared to patients supported with transfusion alone. The overall number needed to treat (NNT) calculated for this group of studies is 4.4 (95 percent CI, 3.6-6.1), which suggests 4 to 5 patients must be treated to spare one patient from transfusion.
- Sensitivity analysis found a smaller magnitude of risk reduction for higher quality studies, which were double-blinded. For higher quality studies, the calculated NNT is 5.2 (95 percent CI, 3.8 to 8.4), and for lower quality studies the calculated NNT is 2.6 (95 percent CI, 2.1 to 3.8). Thus, the higher quality studies predict one patient would avoid transfusion for every five to six patients treated with epoetin, while the lesser quality studies predict one for every two to three treated. There is evidence that in unblinded studies, physicians may be more aggressive in transfusing patients in the control arm, thus overestimating the observed effect of epoetin.
- The strongest evidence for an effect of epoetin on quality of life outcomes is an unpublished randomized double-blinded trial in a patient population with baseline Hb level <10 g/dL, which found significant differences in score changes that favored the epoetin-treated arm for three questions that used visual analog scales (n evaluable=335) and for the Functional Assessment of Cancer Treatment-Anemia (FACT-An) (n evaluable =290). No information is presently available to assess the study protocol for bias resulting from methods used to collect quality-of-life data, or the clinical significance of the reported changes in quality-of-life scores. Eight other published studies, which included a total of 516 evaluable patients, do not provide consistent evidence that epoetin improves quality of life outcomes.
- The most robust evidence that epoetin improves transfusion outcomes for patients undergoing therapy for malignancy compared to transfusion alone comes from trials in patient groups with baseline Hb <10 g/dL. Transfusion outcomes do not appear to be superior in trials where epoetin treatment is initiated in groups of patients who have mean Hb> 10 g/dL compared to trials where mean Hb is <10 g/dL. Among trials on adult patients with baseline Hb <10 g/dL, the range of differences between epoetin and control arms for percentage of patients transfused was 9 percent to 45 percent. For baseline Hb >10 but <12 g/dL, the range was 7 percent to 47 percent; and 7 percent to 39 percent for baseline Hb >12 g/dL.
- The available evidence is not adequate to determine whether outcomes of epoetin treatment are superior when treatment is initiated in groups of patients who have mean Hb> 10 g/dL, compared to groups where mean Hb is <10 g/dL. Randomized controlled trials, double blinded and adequately powered, are necessary to compare the outcomes of epoetin treatment initiated at various Hb thresholds. Inferences from indirect comparison of the results of the available trials can not resolve this question.
- While it is possible that adequately powered comparative trials might demonstrate the superiority of epoetin intervention at the higher Hb levels, our examination of this evidence base suggests two reasons why that may not prove to be true. First, patients whose entry level Hb is below the mean may account for a substantial proportion of transfusions in epoetin-treated patients in trials where baseline Hb is <10 g/dL. Thus the greatest yield for reducing the number of patients transfused in this population might come from initiating epoetin before the Hb level falls substantially below 10, rather than by initiating epoetin treatment at a level substantially above 10 g/dL. Second, in all trials, patients who are unresponsive to epoetin may account for a substantial proportion of patients transfused. Initiating epoetin treatment at a higher Hb level is not expected to reduce transfusions in this subgroup of patients.
In the studies included in this review, does varying the characteristics of the administration of epoetin affect the outcomes of treatment? Are the characteristics of epoetin administration likely to confound the interpretation of the evidence on the relative effects of epoetin treatment according to the alternative Hb thresholds for initiating treatment?
- The meta-analysis examined whether the characteristics of epoetin administration (dosing regimen, treatment duration, and dose range) have an effect on the estimate of the summary odds ratio for transfusion. Only epoetin dose appeared to have an independent effect on transfusion outcomes, but this was potentially confounded by study quality. However, the results of two randomized controlled trials that directly compared lower and higher doses of epoetin (450 vs. 900 units/kg/week) did not demonstrate that the higher dose was superior.
Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?Are there laboratory measurements that can either predict or permit early identification of patients whose anemia responds to epoetin?
- Age. Epoetin is effective in preventing transfusion in pediatric patients. No studies reported outcomes stratified specifically for geriatric patients, but adults up to age 90 were included in some trials.
- Malignant Disease. There is evidence that epoetin produces hematologic responses and probably reduces transfusions in patients with nonmyeloid hematologic malignancies to a similar degree as in patients with tumors of solid organs or tissues.
- Radiotherapy. Although epoetin increases Hb levels for patients managed with radiotherapy alone, mean Hb levels of control patients did not decrease from baseline values. The radiotherapy regimens utilized apparently did not contribute to or exacerbate preexisting mild anemia.
- Platinum Regimens. The evidence demonstrates benefit from epoetin for patients receiving chemotherapy regimens that include either cisplatin or carboplatin, as well as regimens that do not include either of the platinum drugs.
- Predictors of Response. The 22 trials included in this evidence base reported no significant predictors of response to epoetin therapy. In particular, neither baseline serum erythropoietin nor the ratio of observed to predicted serum erythropoietin levels (O/P ratio) predicted response in any analysis.
What are the incidence and severity of adverse effects associated with the use of epoetin and how do these compare with the adverse effects of transfusion?
- Limited evidence on adverse events is available from the studies included in this review, but the frequencies of those reported do not appear to differ markedly between epoetin-treated patients and controls. The only statistically significant difference was a greater frequency of fatigue reported by patients in the control arms.

The literature search identified six controlled trials, all randomized, with a total enrollment of 693 patients that met inclusion criteria for this systematic review. Three trials were placebo-controlled and double-blinded (n=332; 48 percent). Of the 693 patients enrolled, 648 (93.5 percent) were reported as evaluable. Patients in this evidence base had diagnoses known to have a high occurrence of anemia of malignancy (multiple myeloma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and myelodysplastic syndromes -- MDS). With the exception of one trial on patients with MDS, the preponderance of patients in these trials received concurrent therapy for their malignancy.

What are the outcomes of managing anemia with epoetin (plus transfusion when necessary) compared to transfusion alone?What are the relative effects of epoetin treatment according to the alternative hemoglobin thresholds for initiating treatment?
- There is consistent evidence that epoetin increases Hb levels and percent of patients demonstrating hematologic response in patients with anemia of malignancy. The evidence on transfusion outcomes is sparse, but suggests a favorable effect of epoetin treatment.
- The only report on measurements of quality of life is an abstract that does not provide sufficient detail for interpretation of the results.
- All patients included in these studies had baseline hemoglobin <10 g/dL. The evidence does not address alternative thresholds for initiating epoetin treatment in patients with anemia of malignancy.
In the studies included in this review, does varying the characteristics of the administration of epoetin affect the outcomes of treatment?
- The studies suggest that starting doses in the 200-450 units/kg per week range are adequate to achieve hematologic response. However, the only study of patients with MDS used a much higher dose, 1,050 units/kg per week, yet obtained a smaller increase in response rate. The distinct mechanism of anemia in this clonal disorder probably contributes to the reduced response rate.
Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?Are there laboratory measurements that can either predict or permit early identification of patients whose anemia responds to epoetin?
- Malignant disease. A statistically significant hematologic response in the epoetin arm was reported for all hematologic malignancies included in this review. However, the limited evidence available suggests that hematologic response rates are lower for patients with myelodysplastic syndrome.
- Age. All studies are of adults. There are no studies of pediatric patients or studies that separately report on geriatric patients.
- Prior Transfusion. Epoetin increases hematologic responses or Hb levels for patients with either multiple myeloma or non-Hodgkin's lymphoma, irrespective of history of prior transfusion. A single study of MDS patients reported that epoetin increases hematologic responses for patients without previous history of transfusion but not for those previously transfused. History of prior transfusion, however, may be associated with other characteristics, such as duration and progression of disease (which may affect erythropoiesis in MDS patients).
- Predictors of Response. This group of studies does not provide sufficient evidence to draw conclusions on predictors of response. Only the serum concentration of endogenous erythropoietin at baseline and the ratio of observed to expected concentrations of serum erythropoietin (based on the severity of anemia) were reported as significant predictors of response in at least two trials
What are the incidence and severity of adverse effects associated with the use of epoetin, and how do these compare with the adverse effects of transfusion alone?
- Except for hypertension and thromboembolic events, the reported frequency of adverse events does not appear to differ between epoetin-treated patients and controls.

The evidence concerning the use of epoetin after high-dose chemotherapy and allogeneic stem-cell transplantation is derived from 7 controlled studies (total enrollment: 493) of patients that are representative of those undergoing bone marrow-derived allogeneic stem-cell transplantation in clinical practice. Of the 7 controlled trials, all but 2 were randomized (total enrollment in randomized studies: 400); nonrandomized trials compared epoetin-treated patients to historical controls. The largest study enrolled and evaluated 215 patients; all other studies enrolled fewer than 100 patients.

These studies compared the outcomes of transfusion of RBCs initiated at a predefined threshold supplemented with epoetin treatment with the outcomes of RBC transfusion alone. One study exclusively enrolled pediatric patients. Enrolled patients had a variety of hematologic tumors. All studies used bone marrow as the stem-cell source, and all studies administered epoetin intravenously.

Does managing anemia after high-dose chemotherapy and allogeneic stem-cell support using epoetin (with RBC transfusion support initiated at a predefined Hb threshold) improve outcomes compared to managing anemia with RBC transfusion (initiated at a predefined Hb threshold) alone?
- Epoetin consistently results in a statistically significant decrease in the time to RBC engraftment, as indicated by achievement of a predetermined Hb level independent of transfusion support. The range of reduction reported was 1 to 2 weeks. Reticulocyte measures, which tend to predict RBC engraftment, also suggest more rapid engraftment with epoetin administration.
- Outcomes for day of last transfusion are related to and correlate with RBC engraftment by Hb level results, with statistically significant results favoring the epoetin-treated study arm.
- Epoetin administration is unlikely to spare anyone from transfusion, as recipients of HDC/SCS are uniformly anemic following the procedure and response to erythropoetin, (whether endogenous or exogenous) is not immediate. The evidence suggests that epoetin treatment may decrease the number of RBC units transfused.
- Limited evidence suggests that epoetin treatment has no significant effect on length of hospital stay.
Are any characteristics of epoetin administration associated with superior outcomes?
- Transfusion outcomes appear to be associated with the duration of followup for reporting and statistical comparison: shorter followup is more often associated with a significant beneficial effect, whereas longer followup may be complicated by transfusions for graft-versus-host disease and result in nonsignificant outcomes for epoetin.
- For both RBC engraftment and RBC transfusion outcomes, results obtained with epoetin dose extremes (525 or 3,500 units/kg/week) did not appear to differ from those obtained with the moderate doses (700-1,050 units/kg/week) used in the majority of studies.
Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?
- Age. Although only one small study (nonrandomized, historical controls) specifically examined the use of epoetin in a pediatric population, results are consistent with those obtained in all other studies, which enrolled primarily adult populations. Additionally, significant results were obtained in this study using a dose/kg/week that was half or less than the doses used in studies of adult patients.
What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse effects of the transfusion alone?
- There do not appear to be any significant adverse events associated with epoetin treatment in patients receiving allogeneic stem-cell transplants (reporting was sparse, however).
- The available evidence shows no depression of platelet engraftment with epoetin treatment.

The literature search and review for studies of epoetin use after autologous transplantation identified 6 controlled trials (total enrollment: 321). Three of the 6 trials were randomized (total enrollment: 169); nonrandomized trials compared epoetin-treated patients to historical controls. Studies ranged in size from 20 to 114 enrolled patients. All of the studies used bone marrow as the exclusive source of stem cells except for one in which patients with Hodgkin's lymphoma were additionally given peripheral blood-derived stem cells. Although these studies of autologous transplantation do not meet the current standard of care regarding stem-cell source (i.e., peripheral blood stem cells), the results are generalizable to patients undergoing peripheral blood stem-cell transplants.

Does managing anemia after high-dose chemotherapy and autologous stem-cell support using epoetin (with RBC transfusion support initiated at a predefined Hb threshold) improve outcomes compared to managing anemia with RBC transfusion alone?
- The evidence does not support a beneficial effect of epoetin administration on RBC engraftment, RBC transfusion, or length of hospital stay outcomes.
- It is particularly noteworthy that two studies that used the same epoetin protocol for both allogeneic and autologous stem-cell transplant patients reported several outcomes significantly improved for allogeneic stem-cell transplant patients, but not for autologous stem-cell transplant patients.
Are any characteristics of epoetin administration associated with superior outcomes?
- Since the available evidence does not show a clear benefit for epoetin treatment, there is no evidence to favor a particular dose, dosing regimen, or treatment duration.
- Although it is possible that treatment duration was too short in all included studies to significantly improve outcomes, reticulocyte measures (an early indicator of RBC engraftment) did not indicate a probable response.
Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?
- Epoetin did not show a beneficial effect for the entire population of patients treated in these studies. Results among the subpopulations were consistent with overall results, and no subpopulation that derived benefit from epoetin treatment could be identified.
- The lack of response to epoetin in patients given bone marrow stem cells suggests that patients given peripheral blood stem cells also would be unlikely to respond. Preparations of peripheral blood stem cells mobilized with growth factors contain progenitor cells from the erythroid (and other) lineages. These progenitors are farther along the maturation pathway to functional end-stage cells, and may be less dependent on erythropoietin than are unstimulated stem cells harvested from the bone marrow. The time to recovery of red cell counts and correction of anemia thus appears less likely to be shortened by epoetin therapy after infusion of peripheral blood stem cells than after infusion of bone marrow stem cells.
What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse effects of the transfusion alone?
- There do not appear to be any significant adverse events associated with epoetin treatment in patients receiving autologous stem-cell transplants (reporting was sparse, however).
- The available evidence shows no depression of platelet engraftment with epoetin treatment.