Lesson 2. Hematopoietic Growth Factors

Hematopoiesis

continuous production of mature blood cells from hematopoietic stem cells (HSCs)

erythroid, myeloid, megakaryocytic, and lymphoid

Major Lineages of Hematopoiesis

growth factors, cytokines, marrow stromal interactions, transcription factors, and substrate availability

Hematopoiesis Production is regulated by _____________________________

hypoxia, blood loss, infection/inflammation, chemotherapy, and thrombocytopenia

Hematopoiesis demand increases with _______________________________

selected endogenous pathway

Therapeutic Growth Factors amplify ___________________________ rather than directly replacing mature cells.

blood transfusion

So in case of emergency blood loss, injecting drugs that can amplify hematopoiesis is less preferred than _________________________.

Hematopoietic Stem Cells

its self-renewal maintains the stem-cell pool

multiple blood-cell lineages

The Multipotency of Hematopoietic Stem Cells permit differentiation into __________________________.

erythrocytes, megakaryocytes, granulocytes and monocytes

HEMATOPOIETIC STEM CELL DIFFERENTIATION:

1. Common myeloid progenitors generate ____________________________

2. Common lymphoid progenitors generate ___________________________

1 = ?

B cells, T cells, and NK cells

HEMATOPOIETIC STEM CELL DIFFERENTIATION:

1. Common myeloid progenitors generate ____________________________

2. Common lymphoid progenitors generate ___________________________

2 = ?

Hematopoietic Growth Factors

endogenous or recombinant glycoproteins that regulate the survival, proliferation, differentiation, maturation, mobilization, and functional activation of hematopoietic cells

anemia, chemotherapy-induced neutropenia, stem-cell mobilization, thrombocytopenia, and selected marrow-failure states

Pharmacologic Use of Hematopoietic Growth Factors

JAK-STAT

RECEPTOR SIGNALING CLASS:

• Most hematopoietic Growth factors act through a.____________ pathway receptors (Type I cytokine receptor superfamily.

• Ligand binding induces receptor b.____________, activating c._____________, which phosphorylate d.__________________________________ proteins that translocate to the nucleus to regulate gene transcription.

a = ?

dimerization

RECEPTOR SIGNALING CLASS:

• Most hematopoietic Growth factors act through a.____________ pathway receptors (Type I cytokine receptor superfamily.

• Ligand binding induces receptor b.____________, activating c._____________, which phosphorylate d.__________________________________ proteins that translocate to the nucleus to regulate gene transcription.

b = ?

Janus Kinases (JAK2)

RECEPTOR SIGNALING CLASS:

• Most hematopoietic Growth factors act through a.____________ pathway receptors (Type I cytokine receptor superfamily.

• Ligand binding induces receptor b.____________, activating c._____________, which phosphorylate d.__________________________________ proteins that translocate to the nucleus to regulate gene transcription.

c = ?

Signal Transducers and Activators of Transcription (STAT)

RECEPTOR SIGNALING CLASS:

• Most hematopoietic Growth factors act through a.____________ pathway receptors (Type I cytokine receptor superfamily.

• Ligand binding induces receptor b.____________, activating c._____________, which phosphorylate d.__________________________________ proteins that translocate to the nucleus to regulate gene transcription.

d = ?

Erythropoietin (EPO)

REGULATORY NETWORK OF HEMATOPOIESIS:

• principal hormonal regulator of erythropoiesis

G-CSF

REGULATORY NETWORK OF HEMATOPOIESIS:

• major regulator of neutrophil production and mobilization

GM-CSF

REGULATORY NETWORK OF HEMATOPOIESIS:

• broader granulocyte and monocyte/macrophage activity

Thrombopoietin (TPO)

REGULATORY NETWORK OF HEMATOPOIESIS:

• principal regulator of megakaryocyte development and platelet production

Stem-cell factor, IL-3, IL-5, M-CSF, and other cytokines

REGULATORY NETWORK OF HEMATOPOIESIS:

• contribute to progenitor survival and lineage-specific differentiation

Epoetin alfa, Darbepoetin alfa, and related products

CLINICAL CLASSES:

• Erythropoiesis-stimulating agents (ESAs) include:

Filgrastim, Pegfilgrastim, and Sargramostim

CLINICAL CLASSES:

• Myeloid Growth Factors include:

Romiplostim, Eltrombopag

CLINICAL CLASSES:

• Thrombopoietic Agents include:

Oprelvekin (IL-11)

CLINICAL CLASSES:

• Historical/Limited Agents

renal peritubular intestinal cells

Erythropoietin is produced predominantly by __________________________ in adults.

Reduced Tissue Oxygenation (Hypoxia)

ERYTHROPOIETIN (PHYSIOLOGY)

• Primary physiologic stimulus is:

Hypoxia-Inducible Factor (HIF)

ERYTHROPOIETIN (PHYSIOLOGY)

1. Hypoxia stabilizes _______________________________

2. Increased _____________________________

3. Increased erythroid progenitor _________________________

1 = ?

EPO transcription

ERYTHROPOIETIN (PHYSIOLOGY)

1. Hypoxia stabilizes _______________________________

2. Increased _____________________________

3. Increased erythroid progenitor _________________________

2 = ?

survival and proliferation

ERYTHROPOIETIN (PHYSIOLOGY)

1. Hypoxia stabilizes _______________________________

2. Increased _____________________________

3. Increased erythroid progenitor _________________________

3 = ?

RBC mass

ERYTHROPOIETIN (PHYSIOLOGY) — Normal Feedback

1. Increased ______________________

2. Improved ______________________

3. Reduced ______________________

1 = ?

Oxygen delivery

ERYTHROPOIETIN (PHYSIOLOGY) — Normal Feedback

1. Increased ______________________

2. Improved ______________________

3. Reduced ______________________

2 = ?

Hypoxic stimulus

ERYTHROPOIETIN (PHYSIOLOGY) — Normal Feedback

1. Increased ______________________

2. Improved ______________________

3. Reduced ______________________

3 = ?

kidneys

ERYTHROPOIETIN (PHYSIOLOGY) — Normal Feedback

• It is primarily produced in the ____________ wherein in response to hypoxia, it increases erythropoietin production to correct anemia.

kidneys

ERYTHROPOIETIN (PHYSIOLOGY)

• It is primarily produced in the __________ in response to hypoxia wherein there will be increased erythropoietin production to correct anemia

hematocrit and hemoglobin

ERYTHROPOIETIN (PHYSIOLOGY)

• As ________________________ levels drop, erythropoietin levels increase to stimulate more RBC production

Epoetin Alfa

DRUGS THAT TARGET/STIMULATE EPO:

• recombinant human erythropoietin

short-acting

DRUGS THAT TARGET/STIMULATE EPO:

Epoetin Alfa

• They are a a._________________ ESA that is why it is usually given b._________________________.

a = ?

three times a week

DRUGS THAT TARGET/STIMULATE EPO:

Epoetin Alfa

• They are a a._________________ ESA that is why it is usually given b._________________________.

b = ?

anemia associated with chronic kidney disease

DRUGS THAT TARGET/STIMULATE EPO:

Epoetin Alfa

• majorly used in a.___________________________

• also used in selected b.___________________________ and other labeled settings

a = ?

chemotherapy-associated anemia

DRUGS THAT TARGET/STIMULATE EPO:

Epoetin Alfa

• majorly used in a.___________________________

• also used in selected b.___________________________ and other labeled settings

b = ?

iron, folate, vitamin B12, and functional marrow

DRUGS THAT TARGET/STIMULATE EPO:

Epoetin Alfa

• For it to response, it requires adequate a.__________________________

• While using it, you need to monitor the patient’s b.____________________ and clinical response

a = ?

hemoglobin, iron status, blood pressure

DRUGS THAT TARGET/STIMULATE EPO:

Epoetin Alfa

• For it to response, it requires adequate a.__________________________

• While using it, you need to monitor the patient’s b.____________________ and clinical response

b = ?

Darbepoetin Alfa

DRUGS THAT TARGET/STIMULATE EPO:

• engineered erythropoietin analog with additional carbohydrate chains

longer serum half-life

DRUGS THAT TARGET/STIMULATE EPO:

Darbepoetin Alfa

• They have a.________________________ that is why it is adminstered b._________________________.

a = ?

once a week

DRUGS THAT TARGET/STIMULATE EPO:

Darbepoetin Alfa

• They have a.________________________ that is why it is adminstered b._________________________.

b = ?

clinical safety principles

DRUGS THAT TARGET/STIMULATE EPO:

Darbepoetin Alfa

• Their ________________________ are similar to other ESAs.

Methoxypolyethyleneglycol-Epoetin Beta

DRUGS THAT TARGET/STIMULATE EPO:

• they are a Continuous Erythropoietin Receptor Activator (CERA)

long polyethylene glycol polymer

DRUGS THAT TARGET/STIMULATE EPO:

Methoxypolyethyleneglycol-Epoetin Beta

• They are an isoform of erythropoietin attached to a _________________________________.

once every 2 weeks or monthly

DRUGS THAT TARGET/STIMULATE EPO:

Methoxypolyethyleneglycol-Epoetin Beta

• They are administered _________________________________________

Chronic Kidney Disease with Anemia

ESA CLINICAL INDICATIONS:

1. _____________________________ when ESA therapy is appropriate.

2. Selected patients with anemia associated with ____________________________________.

1 = ?

Myelosuppressive chemotherapy

ESA CLINICAL INDICATIONS:

1. _____________________________ when ESA therapy is appropriate.

2. Selected patients with anemia associated with ____________________________________.

2 = ?

urgent RBC transfusion

ESA WARNINGS:

• ESAs are not substitutes for a.__________________________ when immediate correction of b._________________________ is required.

a = ?

oxygen-carrying capacity

ESA WARNINGS:

• ESAs are not substitutes for a.__________________________ when immediate correction of b._________________________ is required.

b = ?

reversible causes of anemia

ESA:

• Always treat a.______________________________ and optimize b.__________________.

a = ?

iron availability

ESA:

• Always treat a.______________________________ and optimize b.__________________.

b = ?

anemia

SIGNIFICANCE OF ESAs:

1. improved the treatment of _____________

2. increasing ____________________________________

3. reducing the need for ______________________

4. enhancing ____________________

1 = ?

hematocrit and hemoglobin levels

SIGNIFICANCE OF ESAs:

1. improved the treatment of _____________

2. increasing ____________________________________

3. reducing the need for ______________________

4. enhancing ____________________

2 = ?

blood transfusions

SIGNIFICANCE OF ESAs:

1. improved the treatment of _____________

2. increasing ____________________________________

3. reducing the need for ______________________

4. enhancing ____________________

3 = ?

quality of life

SIGNIFICANCE OF ESAs:

1. improved the treatment of _____________

2. increasing ____________________________________

3. reducing the need for ______________________

4. enhancing ____________________

4 = ?

Hypertension and Thrombotic Complicaions

ESA ADVERSE EFFECTS:

1. common adverse effects

2. series risks with ESAs

1 = ?

Cardiovascular Events, Thromboembolic Events, Stroke, and Mortality (Hemoglobin >11 g/dL)

ESA ADVERSE EFFECTS:

1. common adverse effects

2. series risks with ESAs

2 = ?

Myeloid Growth Factors

critical in managing neutropenia and enhancing stem cell transplantation, with G-CSF being particularly effective in stem cell mobilization

G-CSF and GM-CSF

MYELOID GROWTH FACTORS:

• Key growth factors used clinically to stimulate white blood cell production

chemotherapy-induced neutropenia

MYELOID GROWTH FACTORS:

G-CSF and GM-CSF

• play vital roles in managing __________________________________, with variations in their structure and pharmacokinetics to suit different clinical needs

febrile neutropenia

CLINICAL APPLICATIONS OF G-CSF:

1. Chemotherapy-induced neutropenia: reduces duration/severity and risk of ______________.

2. ________________ when the chemotherapy regimen and patient factors indicate clinically significant risk.

3. ________________ after a prior neutropenic complication when maintaining chemotherapy intensity is important.

4. ________________ for peripheral blood progenitor-cell collection.

5. Selected ______________________________ syndromes

1 = ?

Primary Prophylaxis

CLINICAL APPLICATIONS OF G-CSF:

1. Chemotherapy-induced neutropenia: reduces duration/severity and risk of ______________.

2. ________________ when the chemotherapy regimen and patient factors indicate clinically significant risk.

3. ________________ after a prior neutropenic complication when maintaining chemotherapy intensity is important.

4. ________________ for peripheral blood progenitor-cell collection.

5. Selected ______________________________ syndromes

2 = ?

Secondary Prophylaxis

CLINICAL APPLICATIONS OF G-CSF:

1. Chemotherapy-induced neutropenia: reduces duration/severity and risk of ______________.

2. ________________ when the chemotherapy regimen and patient factors indicate clinically significant risk.

3. ________________ after a prior neutropenic complication when maintaining chemotherapy intensity is important.

4. ________________ for peripheral blood progenitor-cell collection.

5. Selected ______________________________ syndromes

3 = ?

Stem-cell Mobilization

CLINICAL APPLICATIONS OF G-CSF:

1. Chemotherapy-induced neutropenia: reduces duration/severity and risk of ______________.

2. ________________ when the chemotherapy regimen and patient factors indicate clinically significant risk.

3. ________________ after a prior neutropenic complication when maintaining chemotherapy intensity is important.

4. ________________ for peripheral blood progenitor-cell collection.

5. Selected ______________________________ syndromes

4 = ?

Severe Chronic Neutropenia

CLINICAL APPLICATIONS OF G-CSF:

1. Chemotherapy-induced neutropenia: reduces duration/severity and risk of ______________.

2. ________________ when the chemotherapy regimen and patient factors indicate clinically significant risk.

3. ________________ after a prior neutropenic complication when maintaining chemotherapy intensity is important.

4. ________________ for peripheral blood progenitor-cell collection.

5. Selected ______________________________ syndromes

5 = ?

Filgrastim

RECOMBINANT HUMAN G-CSF:

• rHuG-CSF

bacterial

RECOMBINANT HUMAN G-CSF:

• Filgrastim is produced in __________________ expression systems.

Sargramostim

RECOMBINANT HUMAN G-CSF:

• rHuGM-CSF

yeast

RECOMBINANT HUMAN G-CSF:

• Sargramostim produced in ______________ expression systems.

2-7 hours IV or SC

RECOMBINANT HUMAN G-CSF:

• In Serum Half-Lives, G-CSF and GM-CSF can last up to __________________.

Pegfilgrastim

RECOMBINANT HUMAN G-CSF:

Long-Acting Forms

• a conjugation product of filgrastim and polyethylene glycol

• longer serum half-life allows for single injection per chemotherapy cycle

Lenograstim

RECOMBINANT HUMAN G-CSF:

Long-Acting Forms

• a glycosylated form of recombinant G-CSF

• widely used in Europe

Neutropenia

common side effect of cytotoxic chemotherapy, leading to a higher risk of serious infections

donor granulocytes

A traditional approach in treating neutropenia is transfusing patients with ______________________ but it is often rare and ineffective.

1991

G-CSF Treatment is introduced in _______________ which revolutionized the management of chemotherapy-induced neutropenia.

neutrophil recovery

G-CSF TREATMENT

1. It accelerates __________________________

2. It reduces ______________________________

3. It increases _____________________________

1 = ?

duration of neutropenia

G-CSF TREATMENT

1. It accelerates __________________________

2. It reduces ______________________________

3. It increases _____________________________

2 = ?

nadir neutrophil count

G-CSF TREATMENT

1. It accelerates __________________________

2. It reduces ______________________________

3. It increases _____________________________

3 = ?

febrile neutropenia, antibiotic use, infections, and hospitalization days

G-CSF TREATMENT:

• During trials, G-CSF generally reduces ___________________________.

no significant improvement

G-CSF TREATMENT

• They found out that ___________________________ in overall survival in cancer patients has been demonstrated.

broader myeloid activity

GM-CSF TREATMENT:

• GM-CSF has ___________________________ than G-CSF.

granulocyte and monocyte/macrophage

GM-CSF TREATMENT:

• Stimulates ________________________________ progenitors

mature myeloid cells

GM-CSF TREATMENT:

• Can enhance functions of ___________________________

recombinant GM-CSF

GM-CSF TREATMENT:

• Sargramostim is ___________________

more limited

GM-CSF TREATMENT:

• Clinical use is _______________________ than G-CSF and includes selected myeloid recovery/transplantation settings.

fever induction

GM-CSF TREATMENT:

• Reduces neutropenia duration like G-CSF but is less effective in reducing febrile neutropenia due to potential ___________________________.

Acute Myeloid Leukemia

G-CSF AND GM-CSF USE:

• Approved for _____________________________ treatment, aiding neutrophil recovery and reducing infection and hospitalization

chemotherapy-induced neutropenia

G-CSF AND GM-CSF USE:

• crucial in managing ________________________________, particularly in high-risk patients and those with Acute Myeloid Leukemia

congenital, cyclic, myelodysplasia-associated, and aplastic anemia-related neutropenia

G-CSF AND GM-CSF USE:

• Effective in treating __________________________________________

ADVSERSE EFFECTS OF G-CSF:

1. common side effect resolved after drug discontinuation

2. rare side effect that is a serious risk during a peripheral blood stem cell (PBSC) mobilization

3. if it is _______________________, it has better tolerance and fewer side effects

Splenic Rupture

ADVSERSE EFFECTS OF G-CSF:

1. common side effect resolved after drug discontinuation

2. rare side effect that is a serious risk during a peripheral blood stem cell (PBSC) mobilization

3. if it is _______________________, it has better tolerance and fewer side effects

2 = ?

More frequently

fever, malaise, arthralgias, and myalgias

ADVERSE EFFECTS OF GM-CSF:

1. At higher doses, it can cause ____________________________________

2. ____________________ can lead to peripheral edema and pleural or pericardial effusions

thrombocytopenia

MEGAKARYOCYTE GROWTH FACTORS:

• Patients with a.______________________ face a significant high risk of hemorrhage.

• b.__________________________ is used as a treatment

a = ?