Anemia Due Primarily to Cancer Therapy and Anemia Due Primarily to Malignant Disease

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:

1. 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.
2. Managing anemia without epoetin, using transfusion (usually initiated when hemoglobin decreases to a threshold between 7 and 9 g/dL).
3. 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.)

In this area, four key questions were addressed:

1. What are the outcomes of managing anemia with epoetin compared to transfusion alone? What are the relative effects of epoetin treatment according to the alternative hemoglobin thresholds for initiating treatment?
2. In the studies included in this review, does varying the characteristics of the administration of epoetin affect the outcomes of treatment? The characteristics of epoetin administration are dose, route, dosing regimen (fixed, increasing, or decreasing dose) and treatment duration. Are the characteristics of epoetin administration likely to confound interpretation of the evidence on relative effects of alternative hemoglobin thresholds for initiating epoetin?
3. 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 will respond to epoetin?
4. What are the incidence and severity of adverse effects associated with the use of epoetin, and how do these compare with the adverse affects of transfusion?

Anemia Resulting from Bone-Marrow Ablation Prior to Stem-Cell Transplantation

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:

1. 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.
2. Managing anemia after bone-marrow ablation with transfusion initiated at a predefined Hb threshold.

In this area, four key questions were addressed:

1. Does managing anemia after high-dose chemotherapy and 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?
2. Are any characteristics of epoetin administration associated with superior outcomes? The characteristics of epoetin administration are dose, route, dosing regimen, and treatment duration.
3. Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?
4. What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse affects of the transfusion alone?

Anemia Due Primarily to Cancer Therapy

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 red blood cell 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-blinded (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.
• Hb >10 g/dL.

No trial directly compared the outcomes of initiating epoetin treatment at different Hb thresholds.

1. 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, 3.8-8.4), and for lower quality studies the calculated NNT is 2.6 (95 percent CI, 2.1-3.8). 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 3 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, the impact of missing 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 15 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.

• 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.

2. 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.

3. 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 pre-existing 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.

4. What are the incidence and severity of adverse effects associated with the use of epoetin and how do these compare with the adverse affects 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.

Anemia Due Primarily to Malignant Disease

The literature search identified 6 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). With the exception of one trial on patients with MDS, the preponderance of patients in these trials received concurrent therapy for their malignancy.

1. 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.

2. 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/week range are adequate to achieve hematologic response. However, the only study of patients with myelodysplastic syndrome used a much higher dose, 1,050 units/kg/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.

3. 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 that separately report on geriatric patients.
• Prior transfusion. Epoetin increases hematologic responses or Hb levels for patients with either multiple myeloma or NHL, 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.

4. What are the incidence and severity of adverse effects associated with the use of epoetin, and how do these compare with the adverse affects 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.

Anemia Resulting from Bone-Marrow Ablation Prior to Allogeneic Stem-Cell Transplantation

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 less than 100 patients.

These studies compared the outcomes of transfusion of red blood cells (RBC) 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.

1. 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.

2. 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.

3. 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.

4. What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse affects 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.

Anemia Resulting from Bone-Marrow Ablation Prior to Autologous Stem-Cell Transplantation

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.

1. 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 with 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 which 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.

2. 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.

3. 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.

4. What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse affects 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.