Biology Reference
In-Depth Information
thropoietin receptors (EPOR), rHuEPO therapy appears to be safe in these
patients, without any evident increase in the risk of progression to acute
leukemia. The obstacle to widespread benefit to patients with MDS has been
that higher doses are required than for chemotherapy patients and despite high
doses, only approximately 33% of patients appear to benefit. Intravenous
rHuEPO doses of 210 to 3,200 U/kg/week [51-57] and subcutaneious doses of
150 to 2,100 U/kg/week [58-63] have been studied with an aggregate response
rate of approximately 30%. One strategy to increase response has been the
addition of a myeloid growth factor to rHuEPO therapy in this setting.
Promising results have been reported with recombinant human granulocyte-
macrophage colony-stimulating factor (rHuGM-CSF) [64] and with recombi-
nant human granulocyte colony-stimulating factor (rHuG-CSF) [65, 66] given
simultaneously or sequentially with rHuEPO for anemic patients with MDS. It
is important to note that not all investigators have reported enhance rHuEPO
efficacy in conjunction with myeloid growth factors [67, 68] and that the safe-
ty of maintenance therapy with myeloid growth factors in this patient popula-
tion has not been established. In a randomized, placebo-controlled clinical trial,
150 U/kg/day (approximately 70,000 U/week) rHuEPO produced responses in
37% of treated patients and, at least over an eight-week treatment period, was
not associated with an increased progression to acute leukemia [69].
Taken in aggregate, the available literature suggest that it is a subset of
patients with MDS who appear to benefit from rHuEPO therapy; these patients
typically have refractory anemia without excess of blasts, normal platelet
counts, normal lactate dehydrogenase levels, and a short duration of disease.
This subset of patients probably responds to rHuEPO therapy in a fashion sim-
ilar to that of patients with cancer receiving chemotherapy and it is very rea-
sonable to attempt to relieve transfusion burden or fatigue in this subset of
patients [70, 71].
Future directions
Improvements in clinical trials methodology
As the field moves toward optimizing erythropoietic therapy, more sensitive
endpoints for assessing the relative erythropoietic efficacy of different doses or
schedules of drugs will be required. Until recently, most studies of erythropoi-
etic agents in oncology were designed with a fixed starting dose administered
to all patients, sometimes with a single dose increase permitted for non-respon-
ders. Studies reported a hemoglobin response rate (usually defined as a 2 g/dL
increase in hemoglobin concentration not due to a transfusion) for the drug.
When quality-of-life data emerged suggesting that a hemoglobin concentration
of 12 g/dL may be a particularly important target, later publications expanded
the definition of a hematopoietic response rate to include either a 2 g/dL
increase or an increase to 12 g/dL. There are two issues with this approach to
