Transcript ERYTHROPOEITIC STIMULATING AGENTS

Neel Bhalala (2009)
Sofia Medical University
ERYTHROPOEITIC STIMULATING
AGENTS
Background
 Erythropoiesis-stimulating agents are man-made
versions of a natural protein known as
erythropoietin. Erythropoietin is made by the kidney
and stimulates the primitive cells in the bone
marrow to produce red blood cells, the main oxygencarrying cells in the blood. An increase in the number
of red blood cells is commonly indicated by an
increase in the laboratory measures known as the
blood hemoglobin level and the blood hematocrit.
An abnormally low hemoglobin or hematocrit value
is one of the hallmarks of anemia.
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Background
 Multiple conditions may cause anemia, including the loss of
erythropoietin due to the destruction of kidney function by
chronic kidney disease. Other conditions that may cause
anemia are generally unrelated to a deficiency of
erythropoietin and are exemplified by anemias due to iron
deficiency, certain vitamin deficiencies, hemorrhage, and
various intrinsic bone marrow disorders. Generally,
regardless of the cause of anemia, blood transfusions may
be necessary to relieve patient symptoms and maintain life
when the anemic condition becomes severe. The main goal
of treatment with ESAs is to increase the number of red
blood cells in patients with the specific types of anemia that
are responsive to the ESAs so that blood transfusions are
not needed.
Mechanism of action
 ESA’s stimulates erythropoiesis by the same
mechanism as endogenous erythropoietin. A
primary growth factor for erythroid development,
erythropoietin is produced in the kidney and
released into the bloodstream in response to
hypoxia. In responding to hypoxia, erythropoietin
interacts with progenitor stem cells to increase red
blood cell (RBC) production. Production of
endogenous erythropoietin is impaired in patients
with chronic renal failure (CRF), and erythropoietin
deficiency is the primary cause of their anemia.
Increased hemoglobin levels are not generally
observed until 2 to 6 weeks after initiating treatment
with ESA’s .
BEST (Breast Cancer
Erythropoietin Survival Trial)
 Study Objective
The primary objective of the Breast Cancer
Erythropoietin SurvivalTrial (BEST) was to
determine the effect of maintaining Hb 12 to 14
g/dL with epoetin alfa versus placebo on 12month overall survival. Additional efficacy
variables included change in Hb level from
baseline to study completion, proportion of
patients receiving RBC transfusion, tumor
response rate, and time to disease progression
(TTP).
Results
Results
 The results from the recent survival studies raises the question
about whether erythropoietic agents may negatively affect
survival, especially at high Hb levels. In this study, almost twice as
many patients in the epoetin alfa group than the placebo group
exceeded the target Hb range (Hb > 14 g/dL) at some point during
the study. Although speculative, it may be that the relationship
between Hb and survival is a U-shaped curve, with increased risks
at more extreme Hb levels. It has been suggested that, in certain
tumor cell lines and xenografts that express both erythropoietin
and its receptor, erythropoietin signaling may promote cancer
progression several investigators have suggested a link between
erythropoietin receptor expression and tumor proliferation.
However, many studies showing such signaling required
suprapharmacologic concentrations of erythropoietic agents to
obtain the response and most in vitro studies have shown no such
relationship. No causal relationship between epoetin alfa and
cancer progression in humans has been shown.
Conclusion
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Conclusion:
After reviewing the data it shows that ESA’s increased the risk for death
and serious cardiovascular events when administered to target a hemoglobin of
greater than 12 g/dL. Hence, it is advised that physicians should use the lowest
ESA dose that will gradually increase the hemoglobin level to a concentration
sufficient to avoid the need for blood transfusions. Based upon the new data
which emphasizes the evidence for increased rate of tumor progression it is
indicated that an ESA may offer no benefit and may cause serious harm in
treating anemic cancer patients not currently on chemotherapy. When ESA's
were used to attain hemoglobin levels in excess of the 12 g/dL level there was an
increased risk for serious cardiovascular and thrombotic complications in chronic
renal failure (whether or not receiving dialysis).
ESA's are not indicated for use in specific tumor types (breast cancer, head
and neck cancer, and non-small cell lung cancer). The drug should define a
hemoglobin level in asymptomatic patients at which ESA should be initiated and
the hemoglobin level at which dosing should be suspended that is >12mg/dl. The
ESAs should be discontinued following the completion of a chemotherapy
regimen and re-evaluation of the degree of anemia with subsequent
chemotherapy regimen(s) be done.