Darbepoetin Alfa for Myelodysplastic Syndromes

Clinical trials represent a useful tool to improve our knowledge and, ultimately, our therapeutic practice and, especially in this field, to provide individualized treatment to cancer patients in need.

MDS is a serious disease caused by the production and development of an abnormal number of blood cells by the bone marrow. A number of clinical subtypes occur, and they can be classified loosely based on their pathogenesis, cytogenetics, mutational abnormalities and clinical presentation. There is considerable ambiguity in the vocabulary to describe MDS. A large number of terms have been used in a wide variety of contexts. It is time for consensus and a definite terminology.

A [previous] diagnosis of myelodysplastic syndrome (MDS) does not appear to be an important risk factor for the development of PMF/HM. In MDS, [acquired] cytogenetic abnormalities, increased numbers of circulating blasts and high risk cytogenetic abnormalities are potential risk factors for PMF. Other potential risk factors include smoking and radiotherapy; however, these factors do not appear to account for the higher risk for PMF after previous MDS.

The symptoms of MDS usually begin before the age of 30 years. There is not a specific laboratory test to diagnose MDS. Other symptoms may resemble those of MDS. The mainstay of all three MDSs appears to be marrow blasts as a result of hematopoietic stem cell dysfunction. This may result in symptoms which are not caused by marrow failure, but involve a decreased capacity to produce blood cells. Other causes of abnormal blood cells include aplastic anemia, thalassemia, and sickle cell disease. MDS is an enigmatic disorder that cannot be diagnosed before its symptoms begin. A diagnosis must be made on the basis of history and clinical findings.

There are approximately 4,000 deaths due to MDS in the US every year, excluding deaths on diagnosis due to the disease. The lifetime risk of acquiring MDS is 1/70.5 (2/3.45) and 1/70 (3/3.45) respectively in Caucasians (C) and African-Americans (AA). In AA, the lower risk may reflect the lower prevalence of MDS in the AA population (i.e., a greater genetic predisposition for the disease).

The treatment of myelodysplastic syndromes often consists of induction chemotherapy, consolidation chemotherapy and maintenance therapy. The goal of these treatments is to improve long-term survival. Unfortunately most myelodysplastic syndromes respond poorly to induction chemotherapy, even in cases where marrow blasts are normal.

Overall survival in MDS is low. In the absence of curative treatment, survival is mainly affected by the presence or absence of transformation. Survival is higher if patients with MDS without transformation have long-term survival. We demonstrated the possibility to cure 5% to 7% of patients with MDS.

Most cases of MDS have been estimated to arise on average at the age of 40 - 49 years old. However, some studies found that the mean age of diagnosis is approximately 61 years old. The difference is likely due to age of onset instead of age of diagnosis. The prevalence of MDS increases with age by about 1.02% for every 10-year increase in age.

The most common indication for darbepoetin alfa therapy is prophylaxis for anemia associated with chemotherapy in patients with MDS, and other uses for the drug are still being evaluated. To date, the drug has not been shown to improve outcomes in the treatment of MDS. If darbepoetin alfa proves effective for prophylaxis of chemotherapy-related anemia, then it will likely be the only drug available for this indication. Because the use of darbepoetin alfa is new, there is no available clinical evidence on which to base risks and benefits assessments. There may be potential benefits of this drug.

In a large, double-blind, randomized, placebo-controlled study of darbepoetin alfa in chronic IBD, there was neither significant difference in efficacy nor safety in clinical outcomes compared with a placebo; the results are inconclusive.

There are some unanswered questions related to efficacy of ESA in patients with MDS following the initiation of ESA therapy, particularly in regards to whether patients with myelodysplastic syndromes respond differently to Epo than those with normal karyotypes. Results from a recent paper demonstrates that the use of darbepoetin alfa is associated with a high rate of safety. Despite some concerns regarding its mechanism of action, darbepoetin alfa appears to have the requisite immunomodulatory properties to be efficacious for the treatment and prolongation of MDS.