The reason for the use of erythropoiesis-stimulating agents like EPO in the anemia of chronic disorders (ACD) is the blunted response to EPO, with lower serum levels of EPO detected than would be expected for the observed degree of anemia, together with the reduced sensitivity of red cell progenitors to endogenous EPO seen in ACD. In addition, there are some data to suggest that the use of EPO may reverse the cytokine-mediated inhibition of red cell production.
Recombinant human EPO and its derivatives are widely used in patients with chronic renal failure, patients with cancer undergoing chemotherapy and patients infected with HIV on myelosuppressive anti-retroviral medication. Several different EPOs are currently available or in development: epoetin-alpha (Procrit, Epogen, Eprex), epoetin-β (NeoRecormon) epoetin-δ, biosimilar epoetins (Retacrit, Binocrit, Eporatio), darbepoietin-alpha (Aranesp), and continuous erythropoietin receptor activator (Mircera). In addition, a PEGylated synthetic dimeric peptide capable of binding to and stimulating the EPO receptor, Hematide, is undergoing clinical trials.
Much of the literature relating to the use of EPOs in ACD comes from renal medicine, but there is also evidence that these agents have useful activity in other forms of ACD, for example that seen in rheumatoid arthritis, HIV infection and cancer. Only relatively small studies of EPO usage have been performed in patients with ACD secondary to inflammatory conditions, for example a study by Pincus et al in which four of 13 patients treated with EPO at doses ranging from 50–150 iu/kg thrice weekly showed hematological responses, whereas none of four patients in the placebo arm responded. In another study, 34 patients with inflammatory bowel disease (IBD) refractory to iron therapy were randomly assigned to receive oral iron plus EPO or oral iron and placebo: after 12 weeks, Hb levels had increased by more than 10 g/l in 82% of the patients in the EPO group, as compared with 24% of those in the placebo group. However, the improvement in treatment of inflammatory conditions, such as rheumatoid arthritis or IBD, with anti-inflammatory and disease modifying agents, such as TNF-alpha inhibitors, with associated improvements in Hb levels, means that there is only a limited place for EPOs in their treatment.
There are many more studies of the use of EPO in patients with both solid tumour and hematological malignancies with response rates of 40–80% being seen. Many of these studies describe patients receiving anti-cancer treatment, so the anemia observed may be partly due to the myelosuppressive effects of chemotherapy or radiotherapy, rather than to the inflammatory effects of malignancy alone. However, early studies indicate that, although relative EPO deficiency contributes to the anemia of cancer in patients who are untreated, this effect is increased by the effects of chemotherapy.
Smith et al performed a dose- and schedule determining study in 188 patients with cancer not currently receiving chemotherapy, showing responses in the majority of patients. A recent large systematic review of 46 randomized controlled trials of ESA therapy in patients with cancer concluded that patients receiving EPO had a mean 16.3 g/l higher Hb level than controls, were 18% less likely to require blood transfusions, and had improved health-related quality of life, but survival benefits could not be established.
Responses may be reduced in ACD patients with more marked inflammation or where there is associated iron deficiency, especially in patients with IBD, highlighting both the importance of aiming treatment at the underlying condition and of ensuring replenishment of iron stores in patients who are iron deficient. As discussed previously, it may not always be easy to determine whether patients have ACD alone or ACD with iron deficiency, and evidence is accumulating that iron supplementation may be desirable in many patients treated with EPOs to ensure optimal response.
Predicting which patients with ACD will respond to exogenous EPO would be useful, but although various algorithms incorporating baseline endogenous EPO level, early response indicators and other factors, none of these will reliably predict response, at least in the setting of cancer-related anemia.
Warnings about the Dangers of EPOs
There has recently been mounting concern at possible detrimental effects of EPO administration in ACD, both in terms of cardiovascular risk and thrombosis, and relating to possible risks of tumour recurrence in patients with ACD related to malignancy. The CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study showed that trying to achieve a target Hb level of 135 g/l (compared with 113 g/l) increased the risk of cardiovascular events and did not improve quality of life and the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy), demonstrated that patients with diabetes and chronic kidney disease were at greater risk of stroke following ESA administration and no clear benefit was observed. A randomized study of EPO in patients with non-small cell lung cancer (NSCLC) who were not receiving chemotherapy was terminated prematurely when a higher mortality rate was observed in the group receiving EPO.
These, and other, studies, together with suggestions that some tumour cells might express EPO receptors, raising the possibility that EPO might modulate tumour growth via cytoprotective effects, led the FDA in the United States to recommend that (i) prescribers should use the lowest dose of EPOs that would gradually increase Hb concentration to a level that would avoid the need for transfusion and (ii) treatment with EPOs might increase the risk of serious cardiovascular events and death when administered to produce Hb levels >120 g/l. In addition, the FDA recommends that (iii) EPOs should not be used in specific tumour types (breast, head and neck, NSCLC), nor be administered to patients with active malignancy not receiving chemo- or radiotherapy. Similar conclusions are reached in the updated guidelines published recently by ASH and ASCO.
However, a recent large meta-analysis of over 15,000 patients in 60 studies of EPOs in patients with cancer has shown no evidence that EPOs reduce survival or increase tumor progression in patients with cancer, although some increase in venous thrombembolism was observed. In addition, two recent studies have cast doubt on the idea that EPO receptors may be expressed at significant and clinically relevant levels on non-hematopoietic cells, including tumor cell lines, and it is clear that further, well-designed, clinical trials are necessary to define the role of EPOs in the anemia of malignancy. In the meantime, blood transfusion remains an option for treatment of anemia in patients with contraindicated cancers or those at high risk of venous thromboembolism.