Summary of recommendations
| Recommendation Category . | Recommendation . | |
|---|---|---|
| 2002 . | 2007 . | |
| 1. General recommendation | As in any medical situation, it is essential to give consideration to other correctable causes of anemia before proceeding to 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. Coomb's testing may be appropriate for patients with chronic lymphocytic leukemia; endogenous erythropoietin levels may predict response in patients with myelodysplasia. | 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 auto-immune disease; endogenous erythropoietin levels may predict response in patients with myelodysplasia. Consideration should be given to minimize use of ESAs in patients with high risk of thromboembolic events, as further discussed in Recommendation 4. |
| 2. Special commentary on the comparative effectiveness of epoetin and darbepoetin* | 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 FDA-approved package inserts, the Update Committee considers these agents to be equivalent with respect to effectiveness and safety. | |
| 3. Chemotherapy-induced anemia | ||
| Threshold for initiating ESA therapy, Hb concentration approaching or < 10 g/dL | The use of epoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and a Hb concentration that has declined to a level of ≤ 10 g/dL. RBC transfusion is also a treatment option depending on the severity of anemia or clinical circumstances. | 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 upon the severity of the anemia or clinical circumstances. |
| Initiation threshold, > 10 g/dL but < 12 g/dL | For patients with declining Hb levels but less severe anemia (those with Hb concentration < 12 g/dL, but who never have fallen below 10 g/dL), the decision of whether to use epoetin immediately or to wait until Hb levels fall closer to 10 g/dL should be determined by clinical circumstances. RBC transfusion is also a therapeutic option when warranted by severe clinical conditions. | 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. |
| 4. Thromboembolic risk* | Clinicians should carefully weigh the risks of thromboembolism in patients for whom epoetin or darbepoetin are 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.18 There are no data regarding concomitant use of anticoagulants or aspirin to modulate this risk. | |
| 5. Starting and escalating doses | The recommendations are based on evidence from trials in which epoetin was administered subcutaneously thrice weekly. The recommended starting dose is 150 U/kg thrice weekly for a minimum of 4 wk, with consideration given for dose escalation to 300 U/kg thrice weekly for an additional 4 to 8 wk in those who do not respond to the initial dose. Although supported by less strong evidence, an alternative weekly dosing regimen (40,000 U/wk), based on common clinical practice, can be considered. Dose escalation of weekly regimens should be under similar circumstances to thrice weekly regimens. | The FDA-approved starting dose of epoetin is 150 U/kg TIW or 40,000 U weekly subcutaneously. The FDA-approved starting dose of darbepoetin is 2.25 μg/kg weekly or 500 micrograms every 3 wk 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 FDA-approved labeling (Table 6); no convincing evidence exists to suggest differences in dose escalation schedules are associated with different effectiveness. |
| 6. Discontinuing therapy for no response | Continuing epoetin treatment beyond 6 to 8 wk in the absence of response (eg, < 1–2 g/dL rise in Hb), assuming appropriate dose increase has been attempted in nonresponders, does not appear to be beneficial. Patients who do not respond should be investigated for underlying tumor progression or iron deficiency. As with other failed individual therapeutic trials, consideration should be given to discontinuing the medication. | Continuing epoetin or darbepoetin treatment beyond 6–8 wk in the absence of response (eg, < 1–2 g/dL rise in Hb or no diminution of transfusion requirements), assuming appropriate dose increase has been attempted in non-responders as per the FDA-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. |
| 7. Hb target | Hb levels can be raised to (or near) a concentration of 12 g/dL, at which time the dosage of epoetin should be titrated to maintain that level or restarted when the level falls to near 10 g/dL. Insufficient evidence to date supports the ″normalization″ of Hb levels to above 12 g/dL. | 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 FDA can be found in Table 6 (and Table 6A, based on the November 8, 2007, FDA labeling announcement). Dose reductions are also recommended when Hb rise exceeds 1 g/dL in any 2 wk period or when the Hb exceeds 11 g d/L. Risk of venous thromboembolism should also be considered when determining dose reduction schedules. |
| 8. Iron monitoring and supplementation | 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, maximizing symptomatic improvement for patients, and determining the reason for failure to respond adequately to epoetin. There is inadequate evidence to specify the optimal timing, periodicity, or testing regimen for such monitoring. | There is no change to the recommendation from the 2002 guideline. |
| 9. Anemia in patients not receiving concurrent chemotherapy | There is evidence from one well-designed, placebo-controlled, randomized trial that supports the use of epoetin in patients with anemia associated with low-risk myelodysplasia, but there are no published high-quality studies to support its use in anemic myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients in the absence of chemotherapy. Treatment with epoetin for myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients experiencing chemotherapy-associated anemia should follow the recommendations outlined above. | 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 FDA in March of 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 non-myeloid 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 of 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.″ |
| 10. Treatment of anemia in patients with non-myeloid hematological malignancies who are receiving concurrent chemotherapy | 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 after chemotherapy, epoetin should be used in accordance with the criteria outlined above for chemotherapy-associated anemia if clinically indicated. Blood transfusion is also a therapeutic option. | 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 above. 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. |
| Recommendation Category . | Recommendation . | |
|---|---|---|
| 2002 . | 2007 . | |
| 1. General recommendation | As in any medical situation, it is essential to give consideration to other correctable causes of anemia before proceeding to 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. Coomb's testing may be appropriate for patients with chronic lymphocytic leukemia; endogenous erythropoietin levels may predict response in patients with myelodysplasia. | 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 auto-immune disease; endogenous erythropoietin levels may predict response in patients with myelodysplasia. Consideration should be given to minimize use of ESAs in patients with high risk of thromboembolic events, as further discussed in Recommendation 4. |
| 2. Special commentary on the comparative effectiveness of epoetin and darbepoetin* | 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 FDA-approved package inserts, the Update Committee considers these agents to be equivalent with respect to effectiveness and safety. | |
| 3. Chemotherapy-induced anemia | ||
| Threshold for initiating ESA therapy, Hb concentration approaching or < 10 g/dL | The use of epoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and a Hb concentration that has declined to a level of ≤ 10 g/dL. RBC transfusion is also a treatment option depending on the severity of anemia or clinical circumstances. | 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 upon the severity of the anemia or clinical circumstances. |
| Initiation threshold, > 10 g/dL but < 12 g/dL | For patients with declining Hb levels but less severe anemia (those with Hb concentration < 12 g/dL, but who never have fallen below 10 g/dL), the decision of whether to use epoetin immediately or to wait until Hb levels fall closer to 10 g/dL should be determined by clinical circumstances. RBC transfusion is also a therapeutic option when warranted by severe clinical conditions. | 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. |
| 4. Thromboembolic risk* | Clinicians should carefully weigh the risks of thromboembolism in patients for whom epoetin or darbepoetin are 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.18 There are no data regarding concomitant use of anticoagulants or aspirin to modulate this risk. | |
| 5. Starting and escalating doses | The recommendations are based on evidence from trials in which epoetin was administered subcutaneously thrice weekly. The recommended starting dose is 150 U/kg thrice weekly for a minimum of 4 wk, with consideration given for dose escalation to 300 U/kg thrice weekly for an additional 4 to 8 wk in those who do not respond to the initial dose. Although supported by less strong evidence, an alternative weekly dosing regimen (40,000 U/wk), based on common clinical practice, can be considered. Dose escalation of weekly regimens should be under similar circumstances to thrice weekly regimens. | The FDA-approved starting dose of epoetin is 150 U/kg TIW or 40,000 U weekly subcutaneously. The FDA-approved starting dose of darbepoetin is 2.25 μg/kg weekly or 500 micrograms every 3 wk 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 FDA-approved labeling (Table 6); no convincing evidence exists to suggest differences in dose escalation schedules are associated with different effectiveness. |
| 6. Discontinuing therapy for no response | Continuing epoetin treatment beyond 6 to 8 wk in the absence of response (eg, < 1–2 g/dL rise in Hb), assuming appropriate dose increase has been attempted in nonresponders, does not appear to be beneficial. Patients who do not respond should be investigated for underlying tumor progression or iron deficiency. As with other failed individual therapeutic trials, consideration should be given to discontinuing the medication. | Continuing epoetin or darbepoetin treatment beyond 6–8 wk in the absence of response (eg, < 1–2 g/dL rise in Hb or no diminution of transfusion requirements), assuming appropriate dose increase has been attempted in non-responders as per the FDA-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. |
| 7. Hb target | Hb levels can be raised to (or near) a concentration of 12 g/dL, at which time the dosage of epoetin should be titrated to maintain that level or restarted when the level falls to near 10 g/dL. Insufficient evidence to date supports the ″normalization″ of Hb levels to above 12 g/dL. | 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 FDA can be found in Table 6 (and Table 6A, based on the November 8, 2007, FDA labeling announcement). Dose reductions are also recommended when Hb rise exceeds 1 g/dL in any 2 wk period or when the Hb exceeds 11 g d/L. Risk of venous thromboembolism should also be considered when determining dose reduction schedules. |
| 8. Iron monitoring and supplementation | 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, maximizing symptomatic improvement for patients, and determining the reason for failure to respond adequately to epoetin. There is inadequate evidence to specify the optimal timing, periodicity, or testing regimen for such monitoring. | There is no change to the recommendation from the 2002 guideline. |
| 9. Anemia in patients not receiving concurrent chemotherapy | There is evidence from one well-designed, placebo-controlled, randomized trial that supports the use of epoetin in patients with anemia associated with low-risk myelodysplasia, but there are no published high-quality studies to support its use in anemic myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients in the absence of chemotherapy. Treatment with epoetin for myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients experiencing chemotherapy-associated anemia should follow the recommendations outlined above. | 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 FDA in March of 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 non-myeloid 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 of 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.″ |
| 10. Treatment of anemia in patients with non-myeloid hematological malignancies who are receiving concurrent chemotherapy | 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 after chemotherapy, epoetin should be used in accordance with the criteria outlined above for chemotherapy-associated anemia if clinically indicated. Blood transfusion is also a therapeutic option. | 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 above. 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. |
Bold font indicates differences between the 2002 and 2007 guideline recommendations.
Abbreviations: Hb, hemoglobin; FDA, US Food and Drug Administration.
This topic is new to the guideline.