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 This is an original JCO publication from 2010. Please visit the JCO website to access the full article.


Use of Epoetin and Darbepoetin in Adult Patients With Cancer: An American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) Guideline


 

 Authors
J. Douglas Rizzo, Melissa Brouwers, Patricia Hurley, Jerome Seidenfeld, Murat O. Arcasoy, Jerry L. Spivak, Charles L. Bennett, Julia Bohlius, Darren Evanchuk, Matthew J. Goode, Ann A. Jakubowski, David H. Regan, and Mark R. Somerfield

SUMMARY OF RECOMMENDATIONS

 

 

Recommendation Category2007 Recommendations*2010 Recommendations
I. General RecommendationAs 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 vitamin B12 deficiency where indicated, and assess for occult blood loss and renal insufficiency. Coombs' testing may be appropriate for patients with chronic lymphocytic leukemia or 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 ESAs in patients with high risk of thromboembolic events, as further discussed in Recommendation IV.It is recommended that before any decision regarding use of ESA is made, appropriate history, physical examination, and diagnostic tests be conducted to identify alternative causes of anemia aside from chemotherapy or an underlying hematopoietic malignancy.
  At a minimum, this would include the following: thorough drug exposure history; review of a peripheral-blood smear (and in some cases, a bone marrow examination); analyses, where indicated, for iron, folate, or vitamin B12deficiency; and assessment of reticulocyte count, occult blood loss, and renal insufficiency.
  It may also include the following: Coombs' testing for patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or a history of autoimmune disease; and assessment of endogenous erythropoietin levels for patients with myelodysplastic syndrome.
  Consideration must be given to demonstrated risks of thromboembolism (see Recommendation IV), the possibility of death, and minimizing ESA use, particularly in patients with malignancy being treated with curative intent.
  Special Note: Although the FDA label now limits the indication for ESA use to patients receiving chemotherapy for palliative intent, as described in Literature update and discussion: weighing harms versus benefits, no study has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent. Determination of the goal of treatment requires clinical judgment in many cases.
II. Special Commentary on the Comparative Effectiveness of Epoetin and DarbepoetinBased on a comprehensive systematic review comparing outcomes of epoetin and darbepoetin in patients with chemotherapy-induced anemia and on identical 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.(Unchanged from 2007) 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.
IIIa. Chemotherapy-Induced Anemia: Threshold for Initiating ESA TherapyThe use of epoetin or darbepoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and an Hb concentration that is approaching, or has decreased to less than, 10 g/dL to increase Hb and decrease transfusions. RBC transfusion is also an option, depending on the severity of the anemia or clinical circumstances.The use of epoetin or darbepoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and an Hb concentration that has decreased to less than 10 g/dL to decrease transfusions. RBC transfusion is also an option, depending on the severity of the anemia or clinical circumstances.
IIIb. Chemotherapy-Induced Anemia: Initiating When Hb Is ≥ 10 g/dL but < 12 g/dLFor patients with declining Hb levels but less severe anemia (those with Hb < 12 g/dL, but who have never had Hb decrease to near 10 g/dL), the decision of whether to use epoetin or darbepoetin immediately or to wait until the Hb level decreases closer to 10 g/dLshould 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 those with substantially reduced exercise capacity, energy, or ability to carry out activities of daily living). RBC transfusion is also an option when warranted by clinical conditions.An optimal level at which to initiate ESA therapy in patients with anemia and Hb between 10 and 12 g/dL cannot be definitively determined from the available evidence. Under these circumstances, whether or not to initiate ESA treatment should be determined by clinical judgment, consideration of the risks and benefits of ESAs, and patient preferences (see Recommendations I and IV). RBC transfusion is an option when warranted by clinical conditions.
IV. Thromboembolic RiskClinicians 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 a particularly increased risk. There are no data regarding concomitant use of anticoagulants or aspirin to modulate this risk.(Unchanged from 2007) 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 history of thromboses, surgery, and prolonged periods of immobilization or limited activity. Some diseases and treatment regimens have also been associated with higher risk of venous thromboembolic events.
V. Starting and Modifying DosesThe FDA-approved starting dose of epoetin is 150 U/kg 150 U/kg three times a week or 40,000 U weekly subcutaneously. The FDA-approved starting dose of darbepoetin is 2.25 μg/kg weekly or 500 μg 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 FDA-approved labeling (Table 2); no convincing evidence exists to suggest that differences in dose-escalation schedules are associated with different effectiveness.It is recommended that starting and modifyingdoses of ESA follow FDA guidelines: FDA-approved starting dose of epoetin is 150 U/kg three times a week or 40,000 U weekly subcutaneously; FDA-approved starting dose of darbepoetin is 2.25 μg/kg weekly or 500 μg every 3 weeks subcutaneously; dose modification should follow FDA recommendations as outlined in Table 2; discontinue ESA treatment when chemotherapy concludes
  Evidence does not exist to support improved effectiveness or safety with alternative starting doses, dose schedules, or dose-modifying schedules.
VI. Discontinuing Therapy for No ResponseContinuing epoetin or darbepoetin treatment beyond 6 to 8 weeks in the absence of response (eg, a < 1 to 2 g/dL increase in Hb or no diminution of transfusion requirements) does not seem to be beneficial, assuming an appropriate dose increase has been attempted in nonresponders as per the FDA-approved label, 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.(Unchanged from 2007) Continuing epoetin or darbepoetin treatment beyond 6 to 8 weeks in the absence of response (eg, a < 1 to 2 g/dL increase in Hb or no diminution of transfusion requirements) does not seem to be beneficial, assuming an appropriate dose increase has been attempted in nonresponders as per the FDA-approved label, 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 TargetHb can be increased 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 2. Dose reductions are also recommended when Hb increase exceeds 1 g/dL in any 2-week period or when the Hb exceeds 11 g/dL. Risk of venous thromboembolism should also be considered when determining dose-reduction schedules.Hb can be increased tothe lowest concentration needed to avoid transfusions, which may vary by patient and condition.
  Qualifying Statement: An optimal target Hb concentration cannot be definitively determined from the available literature. Modification to reduce the ESA dose is appropriate when Hbreaches a level sufficient to avoid transfusion or the increase exceeds 1 g/dL in any 2-week period to avoid excessive ESA exposure (see Recommendation V), considering the risks of ESAs (see Recommendation I). Specific dose-reduction recommendations are listed in Table 2.
VIII. Iron Monitoring and SupplementationBaseline 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.(Unchanged from 2007)Baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation, or ferritin levels and instituting iron repletion when indicated may help to reduce the need for ESAs, maximize symptomatic improvement for patients, and determine the reason for failure to respond adequately to ESA therapy. There is inadequate evidence to specify the optimal timing, periodicity, or testing regimen for such monitoring. Although iron replacement is generally recommended to augment response for ESA recipients with iron deficiency, there is insufficient evidence to consider the use of intravenous iron as a standard of care.
IX. Anemia in Patients Not Receiving Concurrent ChemotherapyThere 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 the exclusive use of ESAs in anemic patients with myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia in the absence of concurrent chemotherapy. Analyses of primary data from study 20010103 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 nonmyeloid hematologic 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.”It is recommended that ESAs not be used in treatment of anemia associated with malignancy in patients who are not receiving concurrent myelosuppressive chemotherapy. Use of ESAs in patients with lower risk myelodysplastic syndrome to avoid transfusions is an exception to this recommendation.
X. Treatment of Anemia in Patients With Nonmyeloid Hematologic Malignancies Who Are Receiving Concurrent ChemotherapyPhysicians 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 an increase in Hb is not observed after chemotherapy, treatment with epoetin or darbepoetin for patients with myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia experiencing chemotherapy-associated anemia should follow the recommendations outlined earlier. 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.(Unchanged from 2007) 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 an increase in Hb is not observed after chemotherapy, treatment with epoetin or darbepoetin for patients with myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia experiencing chemotherapy-associated anemia should follow Recommendations I through VIII. 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.
  Special Note: Although the FDA label now limits the indication for ESA use to patients receiving chemotherapy for palliative intent, as described in Literature update and discussion: weighing harms versus benefits, no study has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent. Although patients with multiple myeloma and chronic lymphocytic leukemia often respond to first- or subsequent-line therapy, because these malignancies recur in most patients, determining the treatment intent requires clinical judgment of an individual patient's circumstances.
  • NOTE. The intended use of ESAs is to reduce RBC transfusion requirements. All recommendations are consistent with the FDA labels. Editorial revisions or condensations of earlier text that leave the substance of 2007 recommendations unaltered have been made but are not indicated by font changes.

  • Abbreviations: ESA, erythropoiesis-stimulating agent; FDA, US Food and Drug Administration; Hb, hemoglobin.

  • * Substantive deletions from 2007 guideline appear as bolded text.

  •  Substantive additions in the 2010 guideline recommendations appear as italicized text.

 

 

 

 

 

ASCO Guideline Disclaimer: The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action.  The use of words like “must,” “must not,” “should,” and “should not” indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary.  ASCO provides this information on an “as is” basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.


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