Erythropoietin Leads to Sustained Responses in CAD Patients, European Study Shows

Erythropoietin (EPO) treatment safely promotes sustained increases in hemoglobin levels in people with cold agglutinin disease (CAD) and other autoimmune hemolytic anemias (AIHAs), according to a multicenter study in Europe.

The data pointed to EPO as a safe and effective treatment for CAD, especially if given within the first year following diagnosis, avoiding an excessive use of immunosuppressive therapies.

The study, “Efficacy Of Recombinant Erythropoietin In Autoimmune Haemolytic Anaemia: A Multicentre International Study,” was published in the journal Haematologica.

AIHAs are a group of rare genetic disorders in which the immune system abnormally produces autoantibodies that destroy red blood cells. They are mainly divided into two categories, warm and cold, depending on the autoantibodies’ ideal temperature. CAD is the most common type of cold AIHA.

AIHAs also lead to a reduction in the levels of hemoglobin, the molecule in red blood cells that transports oxygen throughout the body.

A drop in blood oxygen levels leads to the production of the EPO hormone by the kidneys, which in turn will promote the production of blood red cells within the bone barrow to restore blood oxygen balance.

Unusually fast red blood cell production, as is the case in AIHAs, is associated with increased number of immature red blood cells in the blood, an event rarely seen in healthy individuals.

Notably, increasing evidence suggests that AIHA patients may have an inadequate bone marrow response, with 20%–40% of cases showing abnormally low levels of immature red blood cells, which correlate with poor prognosis.

Administration of a lab-made human EPO is widely used as a supportive therapy for CAD in North America but not so much in Europe. However, studies to either support or discourage the use of EPO as a treatment for AIHA are still lacking.

In the new study, researchers evaluated the safety and effectiveness of EPO treatment in 51 AIHA patients treated with EPO at nine centers in Italy, France, Norway, Austria, U.K., Denmark, and the Netherlands.

Participants’ median age was 68, with most (66%) being older than 60. CAD was the most common AIHA type (41% of patients), and five patients had secondary AIHA — caused by other underlying diseases. Severe anemia was present in 37% of cases.

Most patients (90%) had been previously treated with at least one line of therapy, and 67% received EPO treatment due to lack of response to current therapies, including steroids and rituximab.

EPO was given alone or with other therapies at a median of two years after diagnosis and for a median of seven months. Most patients received weekly injections of epoetin alpha (37%) — sold as Epogen, Procrit, Retacrit, and others — or darbepoetin alpha (39%), sold as Aranesp and generic forms.

Before treatment, patients’ median EPO levels were abnormally low in 88% of patients considering their low hemoglobin levels. Still, higher levels of EPO correlated with low amounts of hemoglobin.

Results showed that 55% of patients had partial or complete responses to EPO treatment at 15 days, which increased to 71% at one month, 73% at three months, 76% at six months, and 78% at one year.

This was accompanied by a progressive increase in the proportion of complete responses — defined as hemoglobin levels greater than 12 g/dL and normalized markers of red blood cell damage — reaching about 60% at six months. Most responses were long-lasting, allowing treatment discontinuation in about one-third of responders.

“EPO therapy was able to increase [hemoglobin] levels … in more than 70% of patients, both frontline and in relapsed/refractory chronic disease,” the researchers wrote, adding that this increase was independent of AIHA type or number of previous therapies.

Patients treated with EPO within the first year after diagnosis showed significantly higher response rates (85%) than participants with a longer disease duration (64%). A similar tendency was found for people with primary (77%) versus secondary AIHA (44%).

The differences in effectiveness suggest that the use and duration of immunosuppressive therapies may affect bone marrow responsiveness in AIHA patients, the researchers noted.

Two patients (4%) experienced a thrombotic event, which refers to an obstruction of blood flow due to a blood clot. While EPO treatment may increase the risk of thrombotic events due to a rapid rise in hemoglobin concentrations, other risk factors were present in these patients, the researchers said.

Additional analysis revealed that AIHA patients had higher levels of molecules associated with autoimmunity — IL-6 and IL-17 — and with suppression of blood cell production (TGF-beta), compared with 40 age- and sex-matched healthy individuals.

“All these … abnormalities may play a role in the inflammatory milieu and bone marrow dysregulation of AIHA,” the scientists wrote.

Interestingly, EPO levels in AIHA patients were lower than those reported for people with other types of anemia. The team hypothesized that this may be associated with a naturally slow bone marrow compensation response against fast red blood cell destruction, or the presence of a “stunned bone marrow” unable to provide a prompt response to anemia in AIHA patients.

Therefore, in this patient population, “a temporary EPO stimulation may be preferred to additional immunosuppression,” the investigators wrote.