Note: Differences between the 2002 and 2007 guideline recommendations appear in italicized text.
I. General Recommendation
2007 Recommendation
As in any medical situation, it is essential to consider other correctable causes of anemia before initiating therapy with stimulants of erythropoiesis. Therefore, it is advisable to conduct an appropriate history and physical, and to consider relevant diagnostic testing aimed at identifying causes of anemia aside from chemotherapy or underlying hematopoietic malignancy. At a minimum, one should take a thorough drug exposure history, carefully review the peripheral blood smear (and in some cases, the bone marrow), consider iron, folate, and B12 deficiency where indicated, and assess for occult blood loss and renal insufficiency. Coomb's testing may be appropriate for patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and for those with a history of autoimmune disease; endogenous erythropoietin levels may predict response in patients with myelodysplasia. Consideration should be given to minimize use of erythropoiesis-stimulating agents (ESAs) in patients with high risk of thromboembolic events, as further discussed in Recommendation IV (below).
II. Special Commentary on the Comparative Effectiveness of Epoetin and Darbepoetin (Note: This Topic in New to the Guideline)
2007 Update Committee Statement
Based on a comprehensive systematic review comparing outcomes of epoetin and darbepoetin in patients with chemotherapy induced anemia; and on identical cancer-related indications, warnings, and cautions in the relevant U.S. Food and Drug Administration–approved package inserts, the Update Committee considers these agents to be equivalent with respect to effectiveness and safety.
IIIa. Chemotherapy-Induced Anemia: Threshold for Initiating ESA Therapy (Hemoglobin [Hb] Concentration Approaching or <10 g/dL)
2007 Recommendation
The use of epoetin or darbepoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and a Hb concentration that is approaching, or has fallen below, 10 g/dL, to increase Hb and decrease transfusions. Red blood cell (RBC) transfusion is also an option depending on the severity of the anemia or clinical circumstances.
IIIb. Chemotherapy-Induced Anemia: Initiation Threshold >10 g/dL BUT < 12 g/dL
2007 Recommendation
For patients with declining Hb levels but less severe anemia (those with Hb concentration <12 g/dL, but who have never fallen near 10 g/dL), the decision of whether to use epoetin or darbepoetin immediately or to wait until the Hb levels fall closer to 10 g/dL should be determined by clinical circumstances (including but not limited to elderly individuals with limited cardiopulmonary reserve, those with underlying coronary artery disease or symptomatic angina, or substantially reduced exercise capacity, energy, or ability to carry out activities of daily living [ADLs]). RBC transfusion is also an option when warranted by clinical conditions.
IV. Thromboembolic Risk (Note. This Topic is New to the Guideline)
2007 Recommendation
Clinicians should carefully weigh the risks of thromboembolism in patients for whom epoetin or darbepoetin is prescribed. Randomized clinical trials and systematic reviews of available randomized clinical trials demonstrate an increased risk of thromboembolism in patients receiving epoetin or darbepoetin. Specific risk factors for thromboembolism have not been defined in these trials; therefore, clinicians should use caution and clinical judgment when considering use of these agents. Established, general risk factors for thromboembolic events include previous history of thromboses, surgery, and prolonged periods of immobilization or limited activity. Multiple myeloma patients who are being treated with thalidomide or lenalidomide and doxorubicin or corticosteroids are at increased risk (Bennett et al., 2006). There are no data regarding concomitant use of anticoagulants or aspirin to modulate this risk.
V. Starting and Escalating Doses
2007 Recommendation
The U.S. Food and Drug Administration-approved starting dose of epoetin is 150 U/kg three times per week or 40,000 U weekly subcutaneously. The U.S. Food and Drug Administration–approved starting dose of darbepoetin is 2.25 micrograms/kg weekly or 500 micrograms every 3 weeks subcutaneously. Alternative starting doses or dosing schedules have shown no consistent difference in effectiveness on outcomes including transfusion and Hb response, although they may be considered to improve convenience. Dose escalation should follow U.S. Food and Drug Administration–approved labeling (see table below); no convincing evidence exists to suggest that differences in dose escalation schedules are associated with different effectiveness.
| Table. Erythropoiesis-Stimulating Agent (ESA) Dosing |
| Dose and Modifications |
Epoetin Alfa |
Darbepoetin Alfa |
| Initial dose |
150 U/kg SC TIW |
40,000 U SC weekly |
2.25 micrograms/ kg SC weekly |
500 micrograms SC Q3W |
| Dose increase |
Increase dose to 300 U/kg TIW if no reduction in transfusion requirements or rise in Hb after 8 wk |
Increase dose to 60,000 U SC weekly if no increase in Hb by >1 g/dL after 4 wk of therapy, in the absence of a RBC transfusion |
Increase dose to 4.5 micrograms/ kg if there is <1 g/dL increase in Hb after 6 wk |
--- |
| Dose reductions |
Decrease dose by 25% when Hb reaches a level needed to avoid transfusion or Hb increases >1 g/dL in 2 wk |
Decrease dose by 40% of previous dose when Hb reaches a level needed to avoid transfusion or Hb increases >1 g/dL in 2 wk |
| Dose withholding |
If Hb exceeds 12 g/dL, withhold dose until Hb approaches a level where transfusions may be required; restart dose at 25% below previous dose |
If Hb exceeds 12 g/dL, withhold dose until Hb approaches a level where transfusions may be required; restart dose at 40% below previous dose |
| Abbreviations: ESA, erythropoiesis-stimulating agent; SC, subcutaneous; TIW, three times per week; Q3W, every 3 weeks; Hb, hemoglobin; wk, week; RBC, red blood cell |
VI. Discontinuing Therapy for No Response
2007 Recommendation
Continuing epoetin or darbepoetin treatment beyond 6 to 8 weeks in the absence of response (e.g., <1-2 g/dL rise in Hb or no diminution of transfusion requirements), assuming appropriate dose increase has been attempted in nonresponders as per the U.S. Food and Drug Administration–approved label, does not appear to be beneficial, and ESA therapy should be discontinued. Patients who do not respond should be investigated for underlying tumor progression, iron deficiency, or other etiologies for anemia.
VII. Hb Target
2007 Recommendation
Hb can be raised to (or near) a concentration of 12 g/dL, at which time the dosage of epoetin or darbepoetin should be titrated to maintain that level. Dose and dose modification recommendations recorded in the package insert as of March 2007 and approved by the U.S. Food and Drug Administration (also based on the November 8, 2007, FDA label announcement) can be found in the table above. Dose reductions are also recommended when Hb rise exceeds 1 g/dL in any 2 week period or when the Hb exceeds 11 g d/L. Risk of venous thromboembolism should also be considered when determining dose reduction schedules.
VIII. Iron Monitoring and Supplementation
2007 Recommendation
Baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation, or ferritin levels and instituting iron repletion when indicated, may be valuable in limiting the need for epoetin or darbepoetin, maximizing symptomatic improvement for patients, and determining the reason for failure to respond adequately to ESA therapy. There is inadequate evidence to specify the timing, periodicity, or testing regimen for such monitoring. There is no change to the recommendation from the 2002 guideline.
IX. Anemia in Patients Not Receiving Concurrent Chemotherapy
2007 Recommendation
There is evidence that supports the use of epoetin or darbepoetin in patients with anemia associated with low-risk myelodysplasia. There are no published high-quality studies to support its exclusive use in anemic myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients in the absence of concurrent chemotherapy. Analyses of primary data from Study 20010103 (as yet unpublished) submitted to the U.S. Food and Drug Administration in March 2007, support a stronger recommendation against the use of ESAs to treat anemia associated with malignancy, or the anemia of cancer, among patients with either solid or nonmyeloid hematological malignancies who are not receiving concurrent chemotherapy. This recommendation is consistent with the black-box warning that was added to the prescribing information for both epoetin alfa and darbepoetin in March 2007, as follows: "Use of ESAs increased the risk of death when administered to a target Hb of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated in this population."
X. Treatment of Anemia in Patients with Nonmyeloid Hematological Malignancies Who Are Receiving Concurrent Chemotherapy
2007 Recommendation
Physicians caring for patients with myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia are advised to begin treatment with chemotherapy and/or corticosteroids and observe the hematologic outcomes achieved solely through tumor reduction before considering epoetin. If a rise in Hb is not observed following chemotherapy, treatment with epoetin or darbepoetin for myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients experiencing chemotherapy-associated anemia should follow the recommendations outlined previously. Particular caution should be exercised in the use of epoetin or darbepoetin concomitant with chemotherapeutic agents and diseases where risk of thromboembolic complications is increased. (Refer to Recommendation IV.) Blood transfusion is also a therapeutic option. This recommendation is essentially unchanged from the 2002 guideline. Slight modifications to the recommendation appear in italics.
