Guideline updates use of erythropoiesis-stimulating agents

Issue: November 25, 2010

The American Society of Hematology and the American Society of Clinical Oncology formed an update committee to review data published between January 2007 and January 2010 to analyze the risks and benefits of epoetin and darbepoetin in adults with chemotherapy-induced anemia.

In 2007, the initial guideline was updated to include recommendations addressing safety concerns with the use of darbepoetin alfa. The current update addresses the totality of data on the use of erythropoiesis-stimulating agents, including data published since the 2007 guideline.

The update committee reviewed data on issues relating to ESAs, including tumor progression, venous thromboembolism and survival, but it did not include information on the efficacy of ESAs in reducing transfusions or increasing hemoglobin, as evidence on these outcomes is robust.

The committee attempted to define features of patients with a malignancy who are appropriate candidates for treatment with ESAs and tried to determine the optimal approaches to ESA therapy for patients who are appropriate candidates.

Shorter survival with ESAs

The committee searched Medline and Cochrane databases and identified one new individual patient data meta-analysis, six new literature-based meta-analyses and/or systematic reviews of randomized, controlled trials and 13 publications reporting results from randomized, controlled trials not included in any of the meta-analyses or systematic reviews.

New data since the 2007 guideline update showed that, besides previously proven increased rates of thromboembolic events, therapy with ESAs was associated with shorter survival.

There is still a lack of evidence, however, on the mechanisms of these harms and whether patients are equally at risk or whether some patients may be at minimal risk for harms associated with the use of ESAs compared with red blood cell transfusions alone.

The general recommendation is that clinicians should discuss potential harms and benefits of ESAs and compare those with potential harms and benefits of transfusion for patients undergoing myelotoxic chemotherapy who have hemoglobin levels less than 10 g/dL.

In addition, patient preferences for assumed risk should be included in shared decisions on managing chemotherapy-induced anemia in these patients, according to the committee, which cautioned against the use of ESAs in all other circumstances.

2010 updated recommendations

The 2010 updated recommendations overall are as follows:

Before making a decision regarding the use of ESAs, an appropriate history, physical examination and diagnostic tests should be conducted to identify alternative causes of anemia aside from chemotherapy or an underlying hematopoietic malignancy.
As stated in the 2007 guidelines, based on a comprehensive systematic review comparing outcome of epoetin and darbepoetin in patients with chemotherapy-induced anemia and based on identical indications, warnings and cautions in the relevant FDA-approved package inserts, the committee considers these agents to be equivalent with respect to effectiveness and safety.
The use of epoetin and darbepoetin may be considered for patients with chemotherapy-induced anemia and a hemoglobin concentration that has decreased to less than 10 g/dL to decrease transfusions. Depending on the severity of the anemia or clinical circumstances, red blood cell transfusion is also an option.
Based on available evidence, the optimal level at which to initiate therapy with ESAs in patients with anemia with an hemoglobin level between 10 g/dL and 12 g/dL cannot be definitively determined. Decisions should be based on clinical judgment, risks and benefits and patient preferences. If warranted by clinical conditions, red blood cell transfusion may be an option.
As stated in the 2007 guidelines, clinicians should carefully weigh the risk for thromboembolism in patients for whom epoetin and darbepoetin are prescribed.
Starting and modifying doses of ESAs should follow FDA guidelines: Starting dose of epoetin is 150 U/kg three times a week or 40,000 U weekly subcutaneously; starting dose of darbepoetin is 2.25 mcg/kg weekly or 500 mcg every 3 weeks subcutaneously; dose modification should follow FDA recommendations; and treatment with ESAs should be discontinued when chemotherapy concludes.
As stated in the 2007 guidelines, continuing treatment with epoetin or darbepoetin beyond 6 to 8 weeks in the absence of response does not seem beneficial. Patients not responding should be investigated for underlying tumor progression, iron deficiency or other etiologies for anemia.
Hemoglobin can be increased to the lowest concentration to avoid transfusions; this will vary by patient and condition.
As stated in the 2007 guidelines, baseline and periodic monitoring of iron, total iron-binding capacity, transferring saturation or ferritin levels and instituting iron repletion when indicated may help reduce the need for ESAs, maximize improvement of symptoms and determine the reason for response failure.
ESAs should not be used for the treatment of anemia associated with malignancy in patients who are not receiving concurrent myelosuppressive chemotherapy. An exception to this recommendation is use of ESAs in patients with lower risk myelodysplastic syndrome to avoid transfusions.
As stated in the 2007 guidelines, when treating patients with myeloma, non-Hodgkin’s lymphoma or chronic lymphocytic leukemia, physicians should begin treatment with chemotherapy and/or corticosteroids and observe hematologic outcomes achieved solely through tumor reduction before considering epoetin.

Update committee members said patient counseling regarding the risks and benefits of ESAs is crucial to ensure that patients are making informed decisions. They encouraged health care providers to help patients make informed decisions “by considering the scientific evidence and weighing their individual risks with potential harms and benefits with ESA therapy.”

For more information:

Rizzo JD. Blood. 2010;doi:10.1182/blood-2010-08-300541.