PHARMACOLOGY
HEMATOPOIETIC MEDICATIONS
Dr. Meliton Bato
Outline
o Hematopoietic Growth Factors
o Agents that induce Erythrocyte Production
o Agents that induce Fetal Hemoglobin
o Agents that stimulate Leukocyte Production
o Agents that stimulate Platelet Production
LEGEND
& Book
Recordings
HEMATOPOIETIC GROWTH FACTORS
DIVISIONS:
1. Recombinant or Synthetic growth factor analogues
2. Growth factors used in treating hematopoietic malignancies
• recombinant or synthetic - made in the laboratory, gathered or made
from animals and then injected to humans; indicated with “Rh” sa name
AGENTS THAT INDUCE ERYTHROCYTE PRODUCTION
ERYTHROPOIETIN (EPO)
• from JGA
• good drug to combat some forms of anemia
• number 1 natural hormone and also a cytokine
o Anemia can be from different causes.
o One common indication: CKD
Some Patients with CKD on previous med using recombinant
EPO after few months may develop rebound anemia because
of the anti-EPO antibodies produces.
o Another indication: chemotherapy-induced anemia
§ toxic to bone marrow or kidney directly or inducing a
state of relative resistance to endogenous EPO by
mechanisms involving pro inflammatory cytokines,
oxidative stress, and anti-EPO abs.
o Cancer can also cause anemia via bleeding, poor
nutrition, and bone marrow infiltration
ERYTHROPOIESIS-STIMULATING AGENTS (ESAs)
• Also used in cancer patients
• LIST:
rhEPO (epoietin alfa)
Methoxy PEG-EPO beta
Darbepoietin alfa
- novel erythropoiesis stimulating protein (NESP)
• EPO B w/ Polyethyleneglycol (PEG) – increases the half-life
• MOA: stimulate the EPO receptor and induces
erythropoiesis
• All three ESA are proteins, administered via parentally
o majority are subcutaneous
rhEPO
• increases hematocrit level by at least 6% in half to three
quarters of pts receiving the drug, depending on the anemia
etiology and dose of rhEPO administered.
• rhEPO and darbepoeitin are very similar in structure.
o Difference is number of sialic acid residues attached to
the protein
o More sialic acid groups = higher potency on EPO.
Darbepoietin
• has two extra sialic acid groups à threefold longer half-
life than EPO.
MONTES | PARILLA
Module 4
1
October 2, 2018
MORE ABOUT ERYTHROCYTE PRODUCTION INDUCERS
EPO
• may also play a role in glial and neuronal cell survival
after noxious stimuli exposure or ischemic injury
o Clinical studies on EPO’s neuroprotective effects are
ongoing (tx of stroke when there is ischemic penumbra)
• Administration of EPO to nonanemic or mildly anemic
pts can lead to polycythemia, blood hyperviscosity,
stroke and MI
o 18 young cyclists died unexpectedly due to EPO in
1980s (because it formed clots in the brain)
• 1998-2003: more than 200 pts who received one
formulation of recombinant EPO developed pure red
cell aplasia and neutralizing antibodies against EPO
o Exact cause of immune response is unknown
o A hypothesis involves EPO neo antigens as a result of
partial denaturation of the therapeutic protein
preparation
EPO and Darbepoietin
• may induce HTN
o EPO-induced HTN mechanism is unknown
ESAs
• Clinical studies have shown that pts with anemia + CKD
have a higher risk for serious CVS events, stroke and
death when they are treated with ESAs to target a hgb
> 11 g/Dl
• Current US FDA guidelines: ESAs must be used in CKD
pts when hgb is less than 10 g/dL
o dosing should be individualized to use the lowest dose
of ESA sufficient to reduce the need for erythrocyte
transfusion
• may decrease survival and increase the risk of tumor
progression or recurrence in pts with breast, nonsmall cell
lung, head and neck, lymphoid and cervical Cas
o Potential explanations: EPO receptor expression in
some cancer cells, synergistic toxicity due to
combining EPO therapy with chemotherapy and
radiation therapy, increased thrombogenicity with
elevated Hgb induced with EPO
o This led to FDA altering the label of ESAs that they are
no longer indicated for pts receiving myelosuppresive
chemotherapy administered with curative intent
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PHARMACOLOGY HEMATOPOIETIC MEDICATIONS
AGENTS THAT INDUCE FETAL HEMOGLOBIN (HbF)
Sickle cell disease
• marked by acute pain crises, increased susceptibility to
infection, profound hemolytic anemia
• Newborns and infants with sickle cell disease are
asymptomatic because fetal globin gene expression
persists for many months after birth
• Sickle cell pts aged 2 have 15% HbF and sickle cell
adults have 1-5% HbF
Sickle hemoglobin (HbS)-containing RBCs
• the root cause of these clinical manifestations which begins
in childhood when HbS is first produced
• Adults with high HbF levels experience less frequent crises
and milder anemia hence HbF levels were explored as
therapeutic goals
TWO APPROACHES TO INCREASE HBF:
1. stimulating HbF expression in adults (5-azacytidine and
hydroxyurea)
2. preventing the switch from HbF to HbS (butyrates)
5-AZACYTIDINE &
CONGENER 5-AZA-2’-DEOXYCYTIDINE (DECITABINE)
• DNA methylating agents that increase HbF production to
greater than 20% of total globin expression in pts with sickle
cell anemia and beta- thalassemia
• Theoretical studies suggest that an HbF level of 30-40%
would render pt asymptomatic
• MOA: Reverse DNA methylation of gamma globin gene
• Long-term cancer risk has hindered acceptance as
prophylactic therapy in sickle cell pts
HYDROXYUREA
• aka Hydroxycabazide
• used in the 1990s to treat sickle cell anemia
• MOA: Cytostatic agent that blocks cell division by
inhibiting ribonucleotide reductase
o Mechanism by which hydroxyurea increases HbF
expression is independent of ribonucleotide reductase
inhibition
• Hydroxyurea increases HbF to 20% or more decreases
frequency of sickle cell crises by 50% (4.5 to 2.5 per year
on average)
• Previously been used to treat clonal hematological
disorders (CML and polycythemia vera)
• Relatively safe for long-term administration even in children
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MODULE 4, LECTURE 1
• WBC and platelet suppression was known to be its
main adverse effect
• The induction of HbF by hydroxyurea is slower than that by
5-azacytidine
• Effective in 60% of pts with sickle cell anemia
• Decreases the number of transfusions required by pts who
have three crises/year
• Does not prevent end-organ damage or stroke
• 1998: FDA approved its use for sickle cell anemia
o MOA still unclear
o Current hypothesis: it blocks the division of HbS-
expressing erythroid precursors and triggers reversion
to a fetal pattern of hemoglobin expression in an
attempt to maintain erythrocyte production
BUTYRATES
(ARGININE BUTYRATE & PHENYLBUTYRATE)
• short chain fatty acids
• MOA: inhibit histone deacetylases (enzymes that modify
DNA to make it inaccessible to transcription factors)
• Have increased levels of HbF from 2 to more than 20% in
early clinical trials
• Though butyrates are not effective if the baseline HbF is
less than 1%
• Prevent the switch from HbF to HbS in experimental
animals and children born to DM mothers (whose blood
contains high levels of butyrates)
o However, it does not explain the selectivity of butyrates
for HbF over HbS
AGENTS THAT STIMULATE LEUKOCYTE PRODUCTION
• Main adverse effect: bone pain which resolves after
discontinuation
• Observational studies support an increased risk
Low neutrophil count or neutropenia
• most often a result of interference with progenitor cell
proliferation and differentiation into mature WBCs
(myelosuppression)
• Neutropenia accompanies leukemia and other
malignancies that invade bone marrow and an adverse
effect of chemotherapy
• Less common causes: bone marrow transplant, congenital
neutropenia, HIV or zidovudine-associated neutropenia
Filgrastim (rhG-CSF) and Sargramostim (rhGM-CSF)
• Are almost identical to the natural growth factors G-CSF
and GM-CSF --- recombinant forms
• EFFECT: Dose-independent increase in the absolute
neutrophil count
• Theoretical risk: G-CSF can induce AML or MDS – remains
controversial
GM-CSF
• Is a multilineage growth factor (GF)
• EFFECTS:
o dose-dependent eosinophil count increase
o has ability to increase antitumor activity
• A/E: fever, arthralgia, edema, pleural and pericardial
effusion
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PHARMACOLOGY HEMATOPOIETIC MEDICATIONS MODULE 4, LECTURE 1

GM-CSF and G-CSF • dropped from clinical development because of an excess

• EFFECTS:
o enhance microbicidal neutrophilic activity
o mobilize HSCs from the bone marrow into the
peripheral circulation
• Often used before harvesting peripheral blood stem cells for
transplantation
PEG-filgrastim
• Filgrastim analog conjugated to Polyethylene glycol (PEG)
• metabolized slowly than the native molecule à longer ½ life
• administered as single injection that is equivalent to multiple
daily filgrastim injections
AGENTS THAT STIMULATE PLATELET PRODUCTION
• Recombinant human TPO (rhTPO)
• Pegylated recombinant human megakaryocyte growth
• Development factor (PEG-rHuMGDF)
• Recombinant human IL-11 (rhIL-11 or Oprelvekin)
Low platelet count
• an important adverse effect of many cancer
chemotherapeutic agents
• This limits the doses that can be delivered with acceptable
safety and tolerability
• Complications:
o increased bleeding risk
o increased platelet transfusion requirement
• Platelet transfusion complications:
o febrile reaction
o increased risk infection
o graft versus host disease
ABOUT PLATELET STIMULANTS
• All increase thrombocyte count via dose-dependent manner
• Can stimulate some multipotent as well as committed
precursor cells
• Do not significantly increase hematocrit or WBC count
• Must be administered prophylactically because of a 1-2
week delay
• Cloning of the Thrombopoietin (TPO) gene in 1994 led to
the development of 2 TPO analogues
risk of developing antiTPO autoantibodies which can
suppress natural platelet production
Eltrombopag and Romiplastin
• 2 newer TPO receptor agonists
• USE: Idiopathic Thrombocytopenic Purpura (ITP)
• EFFECTS:
o Both cause transient increase in the platelet count
• Worsening thrombocytopenia may occur after cessation of
medications
• S/E: Bone marrow fibrosis
Eltrombopag
• small molecule TPO receptor agonist
Romiplastin
• recombinant IgG1 Fc-peptide fusion protein that activates
the TPO receptor
Oprevelkin (rhIL-11)
• the only US FDA approved thrombopoietin for the
prevention of severe thrombocytopenia in pts with
myelossuppressive chemotherapy
• Produced in E.coli
• Lacks a N- terminal proline residue
• EFFECT: Dose-dependent increase in platelet count and
megakaryocytes
• Practical goal of treatment: Maintain the platelet count
above 20,000/microliters (150,000 – 450,000/uL is the
normal range) in order to minimize risk of bleeding
• S/E: fatigue, fluid retention, atrial fibrillation
o These adverse side effects are due to the pleiotrophic
effects of this factor on receptors distributed outside the
hematopoietic system
References:
o Powerpoint and Lecture

rhTPO
• first TPO analogue which was full-length, glycosylated
analogue
• rhTPO testing was dropped

PEG-rHuMGDF
• second analogue, N-terminal 163 amino acid TPO
conjugated to polyethylene glycol
• a small trial suggested that this drug was safe to use in
treating thrombocytopenia from AML

rhTPO and PEG-rHuMGDF

• MOA: bind to Mpl (endogenous receptor for TPO named for
its role in murine myeloproliferative leukemia)
• A potential caution: stimulation of platelet production could
lead to thrombosis if platelets are activated
Heavily bioengineered variants of TPO
• i.e. PEG-rHuMGDF
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PHARMACOLOGY HEMATOPOIETIC MEDICATIONS MODULE 4, LECTURE 1

Drug Clinical Application Serious and Common Contraindication Therapeutic

Adverse Effects Consideration
AGENTS THAT STIMULATE ERYTHROCYTE PRODUCTION/ ERYTHROPOIESIS- STIMULATING AGENTS (ESAs)
• MOA: activate the erythropoietin receptor and stimulate erythropoiesis
Erythropoietin • Cancer-associated anemia • Cardiac arrhythmia • Hypersensitivity • Darbepoietin
(Epoetin alfa) • Chemo-induced anemia • Heart failure • Uncontrolled HTN - more sialic acid
• Anemia of CKD • Thrombotic disorder • HTNsive encephalopathy groups (longer half-
• Blood product transfusion • Immune hypersensitivity • Infants life) than epoetin
Methoxy during surgical procedure (HSN) • Neonate alfa
polyethylene • Hypertensive crisis • Pregnant or nursing • PEG–Epoetin beta
glycol (PEG)- • Tumor progression mothers - Has PEG coat for
epoetin beta considerably longer
Edema, Rash, GI upset, half-life than
Headache, Arthralgia, epoetin alfa
Cough, Fever • Consider use when
Hgb of CKD px is
• Epoetin or <10 g/dL
darbepoetin in • Not for curative
nonanemic or mildly myelosuppressive
anemia px causes chemotherapy px
polycythemia, blood • May be abused by
hyperviscosity & stroke athletes
or myocardial infarction
AGENTS THAT INDUCE FETAL HEMOGLOBIN
• MOA: reverse methylation of the gamma globin gene à increased HbF expression (5-azacytidine and decitabine)
block the division of HbS-expressing erythroid precursors à increased HbF expression
5 – Azacytidine • Myelodysplastic syndrome • Atrial fibrillation Hypersensitivity Both interfere with
(MDS) • Heart failure normal DNA synthesis
Decitabine • Myocardial infarction à long-term CA risk
• Sweet’s syndrome
• Anemia
• Febrile neutropenia
• Thrombocytopenia
• Bacteremia
• Intracranial
hemorrhage
• Pleural effusion
• Pulmonary edema
(decitabine only)
• infection

Peripheral edema, heart

Hydroxyurea • Sickle cell anemia
• Refractory chronic myeloid
leukemia (CML)
• Head and neck cancer
• Malignant melanoma
• Ovarian carcinoma
murmur, rash,
hyperglycemia, electrolyte
disturbances, GI upset,
leukopenia, arthralgia,
asthenia, dizziness,
headache, insomnia,
shivering, cough, fatigue,
fever
• Myelosuppression • Hypersensitivity • Mechanism of
• skin ulcer • Severe bone marrow therapeutic effect in
• skin cancer depression cancer treatment
• secondary leukemia appears to involve
inhibition of
ribonucleotide
reductase
• Effect in sickle cell
anemia is unknown

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PHARMACOLOGY HEMATOPOIETIC MEDICATIONS MODULE 4, LECTURE 1

AGENTS THAT STIMULATE LEUKOCYTE PRODUCTION

• MOA: multilineage (GM-CSF) or lineage-specific (G-CSF) growth factors that stimulate myelopoiesis
• Major effect: Raise neutrophil counts; GM-CSF also increases eosinophil counts
Filgrastrim BOTH: Neutropenia BOTH: HSN to E.coli–derived PEG-filgrastrim
(rhG- CSF) • Precipitation of sickle proteins or to drug - a pegylated
Filgrastrim only: peripheral crisis formulation
PEG-filgrastrim blood stem cell harvest • Acute respiratory - longer half-life
distress syndrome
• Splenic rupture G-CSF and GM-CSF
- also enhances the
Filgrastrim only: microbicidal activity of
• skin vasculitis neutrophils
• hemorrhage
• myelodysplastic
syndrome
Sargramostim • Neutropenia • Capillary leak syndrome • HSN to GM-CSF or GM-CSF causes a
(rhGM-CSF) • Peripheral blood stem cell • cardiac arrhythmia yeast-derived products mild and dose-
harvest • pericardial effusion • Concomitant dependent increase
• Myeloid reconstitution after • cerebral hemorrhage chemotherapy or in eosinophils
bone marrow transplant • renal failure radiation therapy (or w/n
24 hours before or after)
Chest pain, rash, • Excess (>10%) leukemic
hypercholesterolemia, myeloid blasts in the
hypomagnesemia, weight blood or bone marrow
loss, GI upset, increased
bilirubin, arthralgia, bone
pain, myalgia, asthenia,
increased blood urea
nitrogen, pharyngitis,
fever, rigor
AGENTS THAT STIMULATE PLATELET PRODUCTION
Eltrombopag • Idiopathic • Hepatotoxicity None • A small-molecule
thrombocytopenic purpura • Bleeding TPO receptor agonist
unresponsive to • Thrombosis
corticosteroids, • Acute renal failure • Orally administered
immunoglobulins, or
splenectomy Nausea, diarrhea,
anemia, fever, myalgia,
• Thrombocytopenia due to fatigue, headache
chronic hepatitis C
Romiplastin Idiopathic thrombocytopenic • Acute myeloid leukemia None • A recombinant IgG
purpura unresponsive to • Bleeding Fc-peptide fusion
corticosteroids, • Thrombosis protein that binds and
immunoglobulins, or • Myelofibrosis activates the TPO
splenectomy receptor
Arthralgia, myalgia,
headache, dizziness, • SC once weekly
insomnia, paresthesia,
URTI, fatigue
Oprelvekin Prevention of severe • Fluid retention Hypersensitivity • Unlike natural IL-11,
(rhIL-11) chemotherapy-induced • Cardiac arrhythmia it lacks the N-terminal
thrombocytopenia • Cardiomegaly proline residue rhIL-
• Hypokalemia 11 à dose-dependent
• Febrile neutropenia increase in the
• Anaphylaxis platelet count and in
the number of
Rash, oral candidiasis, megakaryocytes in
nausea, vomiting, the bone marrow
dizziness, fatigue,
headache, conjunctival
hyperemia, blurred vision,
dyspnea

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