mod 1 slide 1 (intro & hematopoiesis)

innate immune system

• rapid response (hours)

• non-specific response to foreign molecules

• response fixed (non adaptive)

• no immunological memory

adaptive immune system

• delayed response (days)

• highly specific response to antigen

• response adaptive (changes over time)

• immunological memory

innate immunity — first line defenses

• defense against pathogens is mediated by the ____ reactions of innate immunity and the ____ responses of adaptive immunity

• cellular and biochemical defense mechanisms are in place even ____ infection and is poised to respond rapidly to infections

• ______, _______, _______

• early; late

• before

• mechanical, chemical, microbiological

• ______ _____ refers to the ability of the immune system to respond more rapidly and effectively to a pathogen that has been encountered previously

• innate or adaptive?

• immunological memory

• adaptive

hematopoiesis

• all immune cells are derived from what?

• involves differentiation, proliferation, and maturation of cells from which pathways?

• involves _____ of a small population of stem cells

• involves cytokines (interleukins, growth factors), and other chemical mediators — what does this do?

• bone marrow

• myeloid and lymphoid pathways

• self-renewal

• it drives cloning-expansion to cell lineages

immune cell communication and cytokines

• there are 3 modes of cytokine-mediated-cell-to-cell communication — what are they?

• cells communicate through the exchange of ____ ____ in one of 3 modes

1. autocrine (same cell)

2. paracrine (cell to cell — nearby)

3. endocrine (cell to cell — distant)

• secreted cytokines

what is the most obvious cell derived from bone marrow?

• ___ ____ cell type — transport of oxygen via hemoglobin

• RBCs are a ____ resource with a _____ lifespan of about 120 days, and have an intracellular content of about ___ hemoglobin

• RBCs are ____ ___ cells that have ____ ____ ____ including nuclei, ribosomes, mitochondria, and most intracellular machineries during their maturation process

erythrocytes

• most abundant

• renewable; limited; 95%

• terminally differentiated; lost all organelles

ABO blood groups and antigens

• what describes surface glycoproteins on RBCs?

• example: if you are B blood type, you have B-antigens on RBC and circulating antibodies against A-antigens

• if a B recipient is given A type donor blood, an antibody response is mounted against the A blood — incompatible — ______

• antigens

• agglutination

• __ ____ = universal donor

• __ ____ = universal recipient

• O-

• AB+

what you eat displays in your plasma

erythrocytes (RBCs) and erythropoietin (EPO)

• _____ is a glycoprotein hormone that regulates the daily production of 200 billion new RBCs in the human body

• EPO binding to ____ ___ cells promotes their survival, proliferation, and differentiation to mature eryhtrocytes

• EPO production is ____ ___ and is made in the interstitial cells in the ___ ___ in response to anemia, ischemic stress or high altitude

• EPO has ____ function in bone marrow

• erythropoietin (EPO)

• erythroid progenitor

• hypoxia inducible; adult kidney

• endocrine

anemia management in chronic kidney disease (CKD)

• in CKD, anemia is caused by low erythropoietic activity, consistent with ____ ____ __ ____ in the kidneys, leading to inflammation and increased ____ levels — which block ____ ___ ____ and macrophage iron recycling, causing iron restricted erythropoiesis and anemia

• insufficient production of EPO

• hepsidin

• intestinal iron absorption

erythropoietin stimulating agents (ESA)

• ESA’s are indicated for… (5)

anemia associated with…

1. HI infection

2. chemotherapy

3. renal failure

4. CKD

5. iron deficiency

erythropoietin stimulating agents (ESA)

• ESA use found to… (3)

1. significantly raise Hb levels

2. reduce the need for blood transfusions

3. improve hematocrit levels

production, regulation, and utilization of growth factors

• what 2 things represent the current standard of care in patients with anemia in CKD?

  • note: the development of RBCs from bone marrow also requie ____ and ____ ___

• current guidelines support partial treatment of anemia in patients with CKD when Hb level is <___ g/dL

1. ESAs

2. adjuvant IV iron supplementation

• folate; vitamin B12

• 10

ESAs and adverse events

• using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of what?

• the latest product labeling no longer specifies a target Hb level, bute use of what?

• serious adverse cardiovascular events and has not been shown to provide additional patient benefit

• lowest ESA dose sufficient to reduce the need for transfusions

mircera

• methoxy polyethylene glycol-epoetin beta

  • Continuous Erythropoietin Receptor Activator

  • how is the half life?

  • what does PEG modification do to the stability of protein?

  • how is the dosing?

• long half life

• enhances

• once a month (SC injection)

  * anything with PEG = long acting drug and better than predessecor

the short life and quick death of peginesatide (OMONTYS) RIP

• peginesatide is a synthetic peptide-based ESA which was FDA approved in March 2012 for the treatment of ____ in patients with chronic kidney disease

• oncologic drug advisory committee (ODAC) voted 15-1 that peginesatide demonstrated favorable benefit/risk profile

• Feb. 23, 2013: affymax and takeda pharm voluntarily recall OMONTYS injection due to what?

• to date, fatal reaction reported in 0.02% of patients (25,000 patients)

• anemia

• new post-marketing reports of severe hypersensitivity reactions, including anaphylaxis, which can be life-threatening or fatal

daprodustat

• in patients undergoing dialysis, daprodustat was noninferior to ____-____ agents in both hemoglobin levels and MACE

• erythropoiesis-stimulating

2 years ago — FDA approval of JESDUVROQ (daprodustat)

• FDA approved GSK’s anemia frug jesduvroq for kidney disease patients on dialysis

  • daprodustat: first-in-class ___ hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), for the once-a-day treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least 4 months

  • what is the boxed warning?

  • what are the contraindications?

• oral

• same boxed warnings as ESAs

• strong CYP2C8 inhibitors (such as gemfibrozil)

daprodustat: MOA

• daprodustat is a hypoxia-inducible factor (HIF2α) prolyl hydroxyase 2 (PHD2) inhibitor

• HIFs are transcription factors that function as master regulators of what?

• prolyl hydroxylase is enzyme that catalyzes hydroxylation of ___ residue on HIF2α

• oxygen homeostasis

• proline

daprodustat: MOA

• PHD2 is ____ due to lack of oxygen (hypoxia) or in the presence of an inhibitor (top) in these cases, HIF2α is _____ and can ____ ____ ___ ___

• when PDH2 is ____ (bottom) due to sifficient oxygen (normoxic), HIF2α is ____, and consequently recognized by the ____ __ ___, resulting in ____ of HIF2α

  • ubiquitylated HIF2α is then destroyed by the proteasome is then destroyed by the proteasome

  • no HIF2α = no ____ produced

• inactive; functional; induce expression of EPO

• active; hydroxylated; ubiquitin E3 ligase; ubiquitylation

  • EPO

daprodustat: MOA

• hypoxia — or inhibition - HIF is ____

• normoxia - HIP is ____

• stabilized

• degraded

neutrophils

• _____ subpopulation of WBC (65-60% of total WBC count)

• 14 days to mature from stem cell in bone marrow

• _____ — capture and digest bacteria

• _____ (decrease neutrophil count), result of chemotherapy, severe infection and sepsis

• treatment of decrease neutrophil count is accomplished by using what?

• neutrophils classified as ____ or ____ — depending on maturity

• largest

• phagocytes

• neutropenia

• therapeutic growth factor

• band or segmented

chemotherapy - induced neutropenia

• _____ ____ (oncology) target rapidly proliferating cells which include normal hematopoietic cels (bone marrow)

• neutrophils are _____ produced by the bone marrow

• therefore, use of cytotoxic drugs may lead to what?

  • dose-limiting aderse event

• chemotherapeutic agents

• continuously

• neutropenia

how is neutropenia diagnosed?

• neutrophils are measured in terms of an “____ ____ ___“

• contain both band (_____) and segmented (____) neutrophils

• what is the calculation?

• “absolute neutrophil count“ (ANC)

• immature; mature

• total WBC % x total neutrophils (immature and mature)

how is neutropenia diagnosed?

• grade 0 = _____

• grade 4 = ____ ____

• febrile neutropenia = neutropenia + fever > 101 = emergency

• normal

• severe neutropenia

rG-CSF (recombinant granulocyte colony stimulating factor)

• recombinant G-CSF acts to ____ neutrophil proliferation and function while ____ the incidence and severity of neutropenia

• accelerate

• decreasing

rG-CSF (recombinant granulocyte colony stimulating factor)

• what does G-CSF target?

• what are the biologic effects of G-CSF? (3)

• selectively targets neutrophil precursor cells

  1. stimulates proliferation (replication) of neutrophil precursors

  2. enhances differentiation and maturation of neutrophil precursors

  3. activation and enhancement of mature neutrophils

NEUPOGEN

• generic name: Fligrastim

• description: a human recombinant granulocyte colony-stimulating factor (G-CSF)

• indications: cancer patients receiving myelosuppressive chemotherapy or bone marrow transplant; patients with myeloid leukemia; patients with severe neutropenia

informational slide

NEULASTA

• generic name: Pegilgrastim

• description: a covalently linked analog of recombinant G-CSF (filgrastim) and monoethoxypolyethylene glycol (PEG); longer half life

• indications: identical to Neupogen

informational slide

chemotherapy-induced neutropenia (CIN)

• CIN is a major dose-limiting toxicity of systemic cancer chemotherapy — what does it do? (4)

• ____ _____ (FN) — oncologic emergency

  • fever 101ºF or greater + neutropenia

  • often requires hospitalization and broad-spectrum antibiotic use

  • associated with substantial morbidity, mortality, and cost

1. increases risk of infection

2. prompts dose delays/reductions

3. impacts effectiveness

4. impairs quality of life

• febrile neutropenia

occurrence of neutropenic events

• historically, CIN has been considered a ____ ____, with risk increasing over multiple chemotherapy cycles

• recent data in different tumor types have shown that the greatest risk for CIN is in the ____ ____

• cumulative toxicity

• first cycle

  • in patients with breast cancer, most (67%) FN events in the initial placebo group occurred in the first chemotherapy cycle

  • in patients with non-hodgkin’s lymphoma, 50% of FN events occurred in the first chemotherapy cycle

what is the prevention of FN? (4)

1. dose reduction of chemo agents

2. different chemotherapy regimen

3. antibiotic prophylaxis

4. prophylactic colony-stimulating factors (CSFs)

   • Filgratim (Neupogen)

   • Pegfilgrastim (Neulasta)

colony-stimulating factors (CSF)

• _____, _____

  • ↓ incidence of FN by 50%

  • ↓ FN-related hospitalizations and IV anti-infective use

  • ↓ infection-related and all-cause mortality

  • ↑ delivery of planned chemotherapy dose

• dosing

  • _____ — 5 mcg/kg subcutaneously daily x 7-10 days, begin 24-72 hr AFTER chemotherapy

  • _____ — 6 mg (fixed) subcutaneously x 1 dose, given 24-72 hr AFTER chemotherapy

• Fligrastim, Pegfilgrastim

  • Filgrastim

  • Pegfilgrastim

use of antibiotics

• current guidelines recommend antimicrobial prophylaxis with fluoroquinolones in patients at high risk for infection-related ____ and ____, but this practice provides a ___-___ benefit to individual patients

• while fluoroquinolone prophylaxis has reduced some of the collateral damage of intensive chemotherapy, the direct and indirect adverse effect of these agents may ____ ____ ____

• morbidity and mortality; short-term

• limit their utility

eosinophils

• make up 1-3% of total WBC

• mature in ____ ____ for 1-3 days, remain in ____ for minutes, enter ____

• production and activity regulated by: IL-3, IL-4, ____

• eosinophils kill pathogens by doing what?

• eosinophils (increased) associated with allergic reactions, asthma, dermatitis, inflammatory GI disorders

• high concentrations in ____ infections

• bone marrow; blood; tissue

• IL-5

• releasing toxic granules

• parasitic

eosinophils

• eosinophils activation mediated by ___ __ ___

• ____ plays a critical role. in eosinophil differentiation, maturation, recruitment, and activation in tissues

• IL-5 is ____ ____ to eosinophils and has been an important therapeutic target

• other cytokines can also be ____ to mitigate negative eosinophil effector functions

• helper T-cells

• IL-5

• extremely specific

• blocked

eosinophils and asthma

• interleukin-5 (IL-5) exerts selective action on eosinophils, which, in turn, do what?

• interleukin-5 blockers are clinically used and indicated for ___ ____ treatment of patients with sever asthma with an _____ phenotype

• IL-5 blockers reduce asthma exacerbations, improve health-related quality of life, and lung infection

• these treatments roughly ____ the rate of asthma exacerbations in this population

• sustain airway inflammation and worsen asthma symptoms and control

• add-on maintenance; eosinophilic

• halve

Mepolizumab (NUCALA)

• some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with ___-___ ___ ____

• Mepolizumab, a ____ _____ antibody (not fully human) against interleukin-5 (IL-5) (anti-IL-5 MAb), selectively inhibits eosinophilic airway inflammation and induces a significant reduction in sever asthma exacerbations, regardless of IgE levels in blood

• indicated as ____ ____ treatment of patients with severe asthma aged 6 yrs and older, and with an eosinophilic phenotype

  • patients should do what with their current therapy? — which usually includes inhaled corticosteroids

• high-dose inhaled glucocorticoids

• humanized monoclonal

• add-on maintenance

  • should NOT STOP their current therapy

EOHILIA (budesonide oral suspension) for eosinophilic esophagitis (EoE)

• what is EoE?

eosinophilic esophagus — chronic inflammatory disease in the esophagus — can cause dysphagia, regurgitations, stuck food, and chest pain

EOHILIA (budesonide oral suspension) for eosinophilic esophagitis (EoE)

• is budesonide first-in-class?

• is it approved for other indications?

• first in class

• approved for EoE only

EOHILIA (budesonide oral suspension) for eosinophilic esophagitis (EoE)

• how long should patients with EoE take this?

• how do they take it?

• 12 wks

• oral suspension

EOHILIA (budesonide oral suspension) for eosinophilic esophagitis (EoE)

• do you take it with food or water?

no food or water 30 mins before or after

EOHILIA (budesonide oral suspension) for eosinophilic esophagitis (EoE)

• the term “thixotropic“ is used when describing EOHILIA formulation — why is this important for this particular indication?

flows more freely when shaken (lower viscosity) before administration — becomes more viscous when swallowed (able to coat the esophagus and reduce inflammation)