Pooled analysis: Darbepoetin alfa not associated with increased risk for death

Study results conflict with previously released data on ESAs and chemotherapy-induced anemia.

An international study sponsored by Amgen showed that the erythropoiesis-stimulating agent darbepoetin alfa did not increase the risk for death or disease progression in patients with chemotherapy-induced anemia. However, according to Samuel Silver, MD, PhD, results from a meta-analysis conducted by Julia Bohlius, MD, and colleagues released late last year at the American Society for Hematology Annual Meeting are more reliable.

Silver, a member of the HemOnc Today Editorial Board and director of the University of Michigan Cancer Center Network, reviewed both studies. He said the results from Bohlius et al trumped the results published by Heinz Ludwig, MD, of Wilhelminenspital, Vienna, and colleagues in The Journal of Clinical Oncology.

“The Ludwig study has considerably fewer patients — 2,100 as opposed to almost 14,000 in the Bohlius study. In addition, Ludwig is an Amgen-sponsored study, whereas the Bohlius study is done independent of pharma funding,” Silver told HemOnc Today.

The smaller pooled analysis was designed to examine the reported link between ESAs, specifically darbepoetin alfa (Aranesp, Amgen), and an increased risk for death or progression. The analysis included six randomized, placebo-controlled studies. In those studies, patients with chemotherapy-induced anemia were assigned to either darbepoetin alfa (n=1,200) or placebo (n=912). Lung cancers and hematologic cancers were the most common tumor types.

After long-term follow-up, the researchers found little difference in outcome between the two groups. Darbepoetin alfa did not increase OS (HR=0.97; 95% CI, 0.85-1.1), PFS (HR=0.93; 95% CI, 0.84-1.04) or disease progression (HR=0.92; 95% CI, 0.82-1.03).

According to Silver, “they combined mortality during treatment with ESAs and mortality during long-term follow-up, where the Bohlius paper dissects out long-term follow-up and deaths during treatment.

“If you start to look at deaths during long-term follow-up, then it becomes really confounded with progression of the cancer potentially independent of the use of ESAs. When you add these two groups together in a smaller number of patients the study becomes a lot less sensitive to the very issue you’re looking at: What is the association between mortality and erythropoiesis-stimulating agents?” Silver said.

In the study conducted by Bohlius, from the University of Bern, Switzerland, and colleagues, they found that ESAs increased risk for death by 17% during the active study period compared with placebo (95% CI, 1.06-1.30) and worsened overall survival by 6% (HR=1.06, 95% CI, 1.00-1.12). For those undergoing chemotherapy, there was a 10% increased risk for death during the active study period (95% CI, 1.00-1.12) and a 4% increased risk in OS (95% CI, 0.97-1.11). Of note, it is only the overall cancer group that demonstrated a significant risk of death for those patients on ESAs and not the group treated for chemotherapy-associated anemia, although the trends were concerning, Silver said.

The meta-analysis included 13,933 patients from 53 trials, 38 of which included patients undergoing chemotherapy. The results were also recently published in The Lancet.

Bohlius et al also looked at whether physicians were following FDA licensing indications when assigning ESAs and if that played a role in mortality. They concluded that “there was very little evidence” that mortality was impacted whether or not physicians adhered to those indications.

Silver said one cannot draw conclusions about risk from the Ludwig study. He is anxiously awaiting the results of a Canadian study involving about 12,000 patients that explores the mortality risk associated with ESAs, but said the question may never be fully settled.

“Ideally we’d wait for more data to come out from the Bohlius group from additional data mining,” he said. “One would want to do a randomized study with enough patients, where all patients are treated by the FDA guidelines compared with patients treated with transfusions alone, but I don’t think we’ll ever see that study.

“We go with the information that we have: ESAs certainly are appropriate in a palliative setting, and when one is giving chemotherapy in the palliative setting. In the curative setting, you need to have a discussion with your patients about the benefits and risks of transfusions vs. ESAs as best as you can.” – by Jason Harris

Bohlius J. Lancet. 2009;373:1532-1542.

Ludwig H. J Clin Oncol. 2009;doi:10.1200/JCO.2008.19.1130.