ERYTHROPOEITIC STIMULATING AGENTS

1
ERYTHROPOEITIC STIMULATING AGENTS

• Neel Bhalala (2009)
• Sofia Medical University

2
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
  oxygen-carrying 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.

3
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.

4
(No Transcript)
5
Mechanism of action

• ESAs 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 ESAs .

6
BEST (Breast Cancer Erythropoietin Survival
Trial)

• Study ObjectiveThe primary objective of the
  Breast Cancer Erythropoietin Survival Trial
  (BEST) was to determine the effect of maintaining
  Hb 12 to 14 g/dL with epoetin alfa versus placebo
  on 12-month 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).

7
Results
8
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 gt
  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.

9
Conclusion

• Conclusion
• After reviewing the data it shows that ESAs
  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 gt12mg/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.