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Erytropoietin
Past & Future
By: Dr. Abdullah T. Al-Mohamadi
Demnostartor
King Abdulaziz University Hospital
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Today’s Agenda
(●) Definition
(●) Historical background
(●) Structure and Regulation of Erythropoieten
Gene
(●) Epo-sites of production and functions
(●) Erythropoietic stimulating agents
(●) Therapeutic uses
(●) Anemia of chronic kidney disease
(●) Efficacy and benefits in patients with CKD
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Today’s Agenda
(●) Uses of Erythropoietic Stimulating Agents
outside the setting of uremia
(●) Anemia of cancer
(●) ? Safety
(●) Side effects
(●) Peptide Mimetic
(●) Recommendations
(●) Conclusion
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Erythropoietin (EPO)
(●) Endogenous glucoprotein
(●) Member of an extensive cytokine
family that include growth
hormone, prolactin, G-CSF and
others
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Historical Background
(●) Discovered by miyake etal in 1977 from
urine of anemic patients.
(●) Recombinant human EPO (rhuepo)
became available in 1985
(●) (rhuepo) epoetin alfa was introduced
into clinical practice for correction of
anemia of renal failure in 1989.
(●) Jo Douglas Rizzo. Erythropoietin: A paradigm for the development of practice
Guidelines. ASH;2001.
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Production and Functions
(●) 90% produced by a population of
interstitial fibroblasts located in the
kidney’s deep cortex and outer medulla.
(●) less than 10% is produced by the liver.
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Production and Functions: cont.
(●) Hypoxia will cause an exponential increase
in the number of EPO-producing cells i.e
negative feedback loop-low 02=production of
EPO
(●) Epo is not stored within the kidney it is
released as it is formed.
(●) Upon binding of EPO to EPO receptor
autophosphorylation and activation of JAK-2
will occur, thereby triggering the signal
transduction cascade necessary for EPO’s
biologic activity.
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Structure and Regulation of Erythropoietin Gene
(●) Gene is located on chromosome 7
(●) Epo has a compact globular structure
consisting of 4 α-helical bundles has two
domains, necessary for binding to the Epo
receptor.
(●) Transcription of the EPO gene is
regulated by Hypoxia – inducible factora-1
(HIF-1)
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Structure and Regulation of Erythropoietin Gene: cont.
(●) Hypoxia is the fundamental, best
understood
physiologic stimulus of Epo production.
(●) In the absence of hypoxia, Epo expression
is suppressed by degradation of (HIF-1)
(●) Benjamin L et al. Regulation of the Erythropoietin gene. Blood 1999.
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(●) Figure .1.
(●) Figure .2.
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Erythropoietin: cont
(●) The erythroid progenitors and precursors
have the EPO receptors.
(●) Number of receptors in (BFU-E) more than
(CFU-E) and the receptor expression
decreases with erythroid maturation.
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Erythropoietin: cont
(●) EPO is crucial for proliferation and
survival of CFU-Es and their irreversible
terminal differentiation.
● Lawerence et al: Erythropoietin, iron and erythropoiesis: Blood, 2000.
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Figure 3
*EPO-Epo receptor interaction
*Maturation of BFU-E  CFU-E
*EPO mechanism
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Available options for the Management of
Anemia
(●) Red blood cell transfusion
(●) Transfusion related
complications
(●) Transfusion transmitted infection
(●) Immunologic sensitization
(●) Iron overload syndrome
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Available options for the Management of
Anemia: cont.
(●) Volume overload
(●) Transfusion reaction
(●) Immune suppression
(●) Vamvakas, et al. Deleterions Clinical effects of transfusion-Associated Immunomodulation: fact of fiction? Blood 2001;97:1180-93
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(2) Androgen
(●) Side effects of Androgen
(●) Acne
(●) Virilization
(●) Priapism
(●) Peliosis hepatis
(●) Disturbed liver function test
(●) Risk of hepatocellular
carcinoma
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Erythropoietic Stimulating Agents
(
(●) Epoetin alfa
types of rhuepo
(●) Epoetin beta
(●) Darbepoetin alfa ~ long ½ life
)
((●)) Choice between different agents is best
decided by the
(●) practitioner
(●) patient
(●) staff
(●) convenience
(●) compliance
(●) availability
(●) cost
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Therapeutic Uses
(1) Anemia of chronic kidney disease
(●) Mainstay of treatment for anemia of end
stage renal disease.
(●) First FDA approved indication.
(●) Erythropoietic agents are recommended
to stimulate erythropoiesis (Grade 1B)
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Therapeutic Uses: cont.
(●) No prospective randomized studies that
directly compared outcomes with
erythropoietic agents vs. transfusion.
(●) Among hemodialysis patients. It is
administered intravenously rather than
subcutaneously (Grade 2B).
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Anemia of CKD: cont.
(●) Among predialysis and peritoneal
dialysis patients it should be given
subcutaneously rather than
intravenously (Grade 1 B)
● NKF-DOQI Clinical Practice Guidelines for Anemia of Chronic Renal Failure. ANJ Kidney Dis. 2006
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*Criteria*
(1) Initial Hb level of 11/g/dl; or less.
(2) Other treatable causes of anemia should be
excluded or treated if present.
(3) Iron status should be evaluated.
(4) The dose should be titreated slowly.
(5) Targeting Hb level of 12g/dl (Grade 2 C)
~ not targeting Hb levels above 13g/dl;
(Grade 1 B).
● NKF- DOQI Clinical Practice Gudielines for Anemia of Chronic Renal Failure. AMJ Kidney Dis. 2006.
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Efficacy and Benefits in Patients with CKD
(●) A large number of retrospective and
prospective studies have noted the
ability of EPO to raise the Hb level.
*up to 95% response*
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Benefits
(1) Improved quality of life parameters
particularly vitality and sleep.
(2) Increased cognitive function and cerebral
blood flow.
(3) Improve left ventricular function and
exercise-mediated cardiac ischemia.
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Benefits: cont.
(4) Relief a variety of uremic signs and
symptoms, such as sexual dysfunction
in men, and impaired carbohydrate and
cortisol metabolism.
(5) Mobilize iron stores
(●) NKF-DOQI Clinical Practice Guidelines for Anemia of Chronic Renal Failure. AMJ Kidney Dis. 2006.
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Uses of (ESA) Outside the Setting of Uremia
The current applications are many
■ HIV-related anemia
■ Chemotherapy-induced anemia
■ Perisurgical setting
■ Autologous blood collections
■ Anemia of prematurity
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Uses of (ESA) Outside the Setting of
Uremia: cont.
■ Anemia of cancer
■ Anemia associated with MM
■ Anemia associated with non-Hodgkin lymphoma
■ Acceleration of erythroid repopulation after
allogeneic BMT
■ Hyporegenerative anemia in patients
undergoing organ transplantation and receiving
cyclosporin A to avoid rejection
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Uses of ESA Outside the Setting of Uremia
■ Adjuvant for phlebotomy
■ Anemia of rheumatoid arthritis
■ Anemia of inflammatory bowel disease.
■ Anemia in Jehova’s witness
■ Pure RBC aplasia, MDS
■ Induction of Hb F synthesis in SCA and
Thalassemia.
■ Orthostatic hypotention
■ Mario Cazzola et al. Use of recombinant Human erythropoietin outside the setting of uremia. Blood
Vol. 89, 1997.
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FDA approved indications
(1) Anemia related to therapy with AZT in
HIV infected patients
(2) Anemia in patients with non-myeloid
malignancies where anemia is due to the
effect of concomitantly administered
chemotherapy.
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FDA approved indications: cont.
(3) The treatment of anemia in patients
scheduled to undergo elective, non- cardiac,
non-vascular surgery to reduce the need for
allogenetic blood transfusion.
(4) Patients at high risk of perioperative
transfusions with significant anticipated
blood loss.
J. Douglas Rizzo. Erythropoietin: A Paradigm for the development of Practice Guidelines ASH 2001
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Anemia of Cancer*ASH/ASCO/NCCN
EORTC Guidelines
■ (rhuepo) approved for use in 1993 40-50% of patients
with solid tumors and 60-70% of patients with
hematologic malignancies are anemic at the time
of diagnosis.
■ Data suggests that anemia in cancer patients
is vastly under recognized and under treated.
■ Fatigue is the most reported limiting symptom.
■ Adversely affects the QOL.
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Anemia of Cancer*ASH/ASCO/NCCN
EORTC Guidelines: cont.
■ Exclude other causes of anemia.
■ Assessment and periodic monitoring of iron store is
indicated.
■ Support treating anemia in cancer patients with Hb
level of 9-11g/dl to target Hb levels of 12g/dl.
■ Minimize transfusion requirement and resolve
clinical symptoms associated with anemia.
■ New EORTC guidelines for the treatment of anemia in patients with cancer:2005
■ NCCN Practice Guidelines in Oncology: Cancer and Treatment Related Anemia 2006.
■ J. Douglas R et al. EErythopoietin: A paradigm for the development of Practice Guidelines. ASH:2001.
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Anemia of Cancer*ASH/ASCO/NCCN
EORTC Guidelines: cont.
●Titration of ESAS to the lowest effective
maintenance dose, adjusting symptoms
rather than Hb levels.
● Data from different kind of studies provide
support that ESA results in statically
significant mean Hb increase of above
1g/dl after 4 weeks and 2 g/dl after 8 weeks.
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Anemia of Cancer*ASH/ASCO/NCCN
EORTC Guidelines: cont.
● Continuing treatment beyond 6 to 8
weeks in the absence of response dose
not appear to be beneficial.
● Response rates up to 75%
●
Gernot B et al. Risks and Benefits of Erythropiesis-Stimulating Agents in Cancer
Management. Seminars in Hematology 2007.
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Safety of Erythropoietic Agents
Overview
● Data continue to accumulate regarding
the increased risk of mortality and of
possible tumor promotion.
● As of March, 2007 increased mortality has
been observed…when strategies were
designed to achieve and maintain Hb level
above 12g/dl.
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Safety of Erythropoietic Agents
Overview: cont.
● Metastatic breast cancer , head and
neck cancer~a trend toward higher
mortality among patients receiving
the drug.
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FDA Warning Letter
● There are insufficient data from adequate
and well controlled studies designed to
assess effects on survival or tumor
promotion.
● Reconsideration of risks benefit ratio.
● FDA label update 11-08-2007.
● FDA patient information.
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Possible effects on the course of underlying
disease.
(●) EPO receptors are found on several malignant cell
lines eg. head and neck, lung, ovarian, breast
uterine, prostate, hepatocellular and renal cell
carcinoma.
(●) Induction of EPO receptors were associated with
neoangiogenesis, tumor hypoxia and infiltrating
tumors, ↓ loco regional control.
(●) Increased thrombovascular events with increased
morbidity and potential increased mortality.
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Conclusion
● Over treatment of anemia to a Hb more
than 12g/dl as well as insufficient
treatment have each been associated
with unfavorable clinical courses.
● FDA says use minimum dose possible
to get Hb no higher than 12g/dl and stop
one chemotherapy have been completed.
● Patients should be well informed about
possible side effects and survival
disadvantage.
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Therapeutic Abuses
● Used in sports to improve endurance
● Now detected from naturally occurring
EPO by protein markers appearing
post injection.
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Clinically Relevant Side Effects
■ Safe and well tolerated
(●) Hypertension
In 20-30% after IV administration~less
likely after subcuntaneous use. Mostly in
chronic renal failure.
(●) Hypertensive encephalopathy and seizures
may occur when EPO causes a rapid rise
in BP.
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Clinically Relevant Effects: cont.
(●) Thrombotic and cardiovascular events are
rare~target Hb >12g/dl
(●)
200 patients were treatd with Eprex in
European countries from 1998-2004 had pure
red cell aplasia. This complication is now
encountered rarely and was probably caused by
defective formulation rather than inherent
antigenicity.
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Small Molecule EPO Mimetics
(●) Synthesized from random peptide (libraries) displayed
on filamentous phage (bacterial virus)
(●) It is 14-20 a.a in lengths can bind to Epo receptors and
activate signal transduction cascade.
(●) “Hematide” is peptide that has been developed, stable
pegylated with long ½ life. It is now being evaluated in
phase 2 both in renal patients and patient with cancer.
(●) Safe, well tolerated and without unwanted
immunological side effects.
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Concerns and Caveats
(●)
It has become increasingly apparent that EPOR is present on a wide
range of normal cells with possible beneficial effects.
Thought to protect neural network by NF - Kappa β stimulation.
Evidence that neuroprotective nature of EPO is useful post-CVA
May be used in treatment of stroke victims.
(●) There is concern that EPO may contribute to the
pathogenesis of proliferative diabetic retinopathy through
stimulation and proliferation and migration of vascular
endothelial cells.
(●) H. Franklin Bun. New agents that stimulate Erythropoiesis. Blood, 1 Feb. 2007.
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???
Cost
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Conclusion
●Take Home Messages●
(●) Two decade ago, recombinent human
erythroprotein was introduced into clinical,
practice, now millions of patient throughout
the
world are receiving it.
(●) Administration of recombinent human
erythropoietin should be to patients who are
very
likely to respond and benefit from this
treatment.
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Conclusion: cont.
(●) Demanding a well designed trails to address
safety issue in cancer patient with chemotherapy
associated anemia using currently approved
dosing regimens in generalizable tumor type.
(●) The search goes on for orally active antianemic
therapies, better tolerated and hopefully, much
less costly.
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Conclusion: cont.
(●) A growing body of evidence indicates that
EPO has tissue protective effects and
prevent tissue damage during ischemia
and inflammation.
(●) Cost: benefit ratio to the use of ESA
needs to be refined and validated for many
indication.
(●) Evidence based Guidelines for other clinical
applications are warranted