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Oncology Exam 2
Smith Medications for Neutropenia (B)
| Term | Definition |
|---|---|
| Review from 1st class: T/F: Epoetin Alfa is produced by inserting the unaltered human erythropoietin gene into a mammalian cell | True |
| Myeloid growth factor product for GM-CSF is? | Sargramostim |
| Myeloid growth factor products for G-CSF are? | -Filgrastim -Pegfilgrastim -Efbemalenograstim Alfa -Eflapegrastim-xnst |
| For our GM-CSF we have one product Sargramostim—> | 127 amino acid glycoprotein produced in yeast • Gene for human GM-CSF has been modified so a there is a substitution of leucine at position 23, resulting in changed glycosylations • Primary effect is to stimulate myelopoiesis *produced in yeast so its different from our ESA |
| Sargramostim—> when we are making this product, we are “tweaking” the gene for ______ _______ just a little (change the DNA in such a way that we get a change in AA at the position ___. *change in leucine resulting in an additional glycosylation to this GM-CFS produced by the yeast compared to that produced by our own bodies. | human GSF; 23 *Primary reason why we use Sargramostim is we’re trying to stimulate myelopoesis (production of WBC). Remember that GM-CSF is working high up in the hematopoesis chart |
| What is the MOA of Sargramostim? | Stimulates proliferation, differentiation, and function of several myeloid cell lines -Stimulates CFU-GEMM, CFU-GM, CFU-M, CFU-E, and CFU-Meg -Enhances migration, phagocytosis, superoxide production, and antibody-dependent cell-mediated toxicity of neutrophils, monocytes, and eosinophils -Acts synergistically with other hematopoietic growth factors |
| MOA Sargramostim (Smith): once this drug finds the receptor on those pre-mature WBC, its going stimulate them to proliferate/differentiate and its going find all these different populations of precursor cells which includes? | CFU-GEMM, CFU-GM, CFU-M, CFU-E, and CFU-Meg *just know that Sargramostim is going to be hitting a lot of those CFUs throughout the hemopoetic scheme on the MYELOID side of blood cell development |
| Sargramostim enhances the activity of WBC once they are out in circulation enhancing: | (migration, phagocytosis, superoxide production, and antibody-dependent cell mediated toxicity of neutrophils, monocytes, and eosinophils) *know that Sargramostim is one of our growth factors in the hematopoietic scheme that interacts with all sorts of those colony forming units and its acting synergistically with other hematopoietic growth factors |
| Sargramostim PK: this drug is given: | SQ or slow IV; 1/2 life is 2-3h; IV infusion should be over 3-6hr; *IV infusion is slower due to adverse responses people get as they receive their IV medication |
| Sargramostim Phamacodynamics: Why do we see a drop in absolute leukocyte count? | See a decrease b/c sargramstim is stimulating some of the activity that WBC normally do, and what’s happening is your getting those WBC “marginating” (moving to the sides of the blood vessels b/c those WBC think they need to go out of the bloodstream into the body into the tissue somewhere and fight some sort of infection. |
| Sargramostim PD Dose (may get dependent biphasic increase in leukocyte counts)—> | After the decrease in absolute leukocyte count, we then see a response to the medication—> increase in the # of new WBC being formed and that happens in a dose-dependent BIPHASIC manner. Similar to production of RBC, you get a “bump” in those almost mature WBC, get pushed our of the bone marrow and that is the first initial phase increase in WBC # and then wait for Sargramostim action to get those blood cells proliferating/differentiatng and release into circulation. |
| Sargramostim PD: when you D/C this medication, you will see leukocyte counts fall back to the pt’s baseline within ___ -__ days. | 2-10 days |
| We tend to dose this drug in 2 different ways: 1. If you’re trying to ONLY increase your neutrophil count and don’t care so much about granulocytes that will also be stimulated to be produced by this drug you will use _______ doses of Sargraostim to increase your neutrophils. 2. Trying to increase other WBC like eosinophils use _______ doses | LOWER (primarily neutrophilic); higher *with this drug we’re really just interested in increasing neutrophil count, so overtime, we tend to use lower doses to help fight any bacterial infections they get. |
| Sargramostim PD: we have to monitor? | -blood counts to avoid excessive rise in granulocyte count *don’t overshoot and only to the target your trying to get for the neutrophil count |
| Sargramostim AE include: | Bone pain, malaise, flu-like symptoms, fever, diarrhea, dyspnea, and rash • Acute reaction to first dose (flushing, hypotension, nausea, vomiting, dyspnea, fall in arterial oxygen sat due to granulocyte sequestration in pulmonary circulation) • Capillary leak syndrome • Serious adverse effects: transient supraventricular arrhythmia, dyspnea, elevation of serum creatinine, bilirubin, and hepatic enzymes |
| One of the most significant AE of Sargramostim is the bone pain, why? | b/c synthesis starts in the bone marrow,; |
| Pts taking Sargramostim for the first time may get an ____ _____ | acute rxn; (common flushing, fever, Hypotension, nausea, vomiting, etc. help with premedication |
| Pts on Sargramostim may also experience _____ ________ ____. Integrity is comproised and people end up with EDEMA. | capillary leak syndrome |
| What are the biologicals we use for G-CSF? | -Filgrastim -Pegfilgrastim -Efbemalenograstim Alfa -Eflapegrastim-xnst |
| G-CSF is a growth factor produced by our bodies, what cell is primarily being increased with G-CSF agents? Single or pluripotent? | Neutrophils; Single-lineage growth factor (only stimulating Neutrophils) |
| Filgrastim, a G-CSF biological is a? | Recombinant human G-CSF • 175-amino acid glycoprotein produced in E. coli • Unlike natural G-CSF, it is not glycosylated and carries an extra N-terminal methionine • Principle action: stimulation of CFU-G to increase neutrophil production |
| This product is produced in E. Coli (we put the human gene for G-CSF into E. Coli bacteria, because we are popping it into a bacteria, its NOT going to do Glycosylation since there is no machinery for that in bacteria, diffferent from the yeast and Chinese hamster). | Filgrastim |
| When the bacteria are injected with the recombinant human G-CSF, they form the G-CSF protein but they put an extra methionine on the __-______ | N-terminal; |
| Purpose of Filgrastim is to stimulate the _______ count and its working on that CFU-G that’s further down the hematopoetic diagram | neutrophil |
| MOA of Filgrastim is? | Binds to G-CSF receptor on surface of immature neutrophils and mature neutrophile • Little effect on monocytes, macrophages, eosinophils • Enhances neutrophil phagocytosis and cytotoxicity • Reduces inflammation by Inhibiting IL-2, tumor necrosis factor, and interferon gamma • Mobilizes primitive hematopoietic stem cells |
| PK and AE of Filgrastim? | Pharmacokinetics (SQ or IV over at least 30 mins; T1/2=3.5 hours) AE—> Prolonged high doses: mild to moderate bone pain, local skin reactions, acute cutaneous necrotizing vasculitis; -Prolonged use: Marked granulocytosis (counts over 100,000/uL) and mild to moderate splenomegaly; -Contraindicated in patients with history of sensitivity to drugs produced in E. coli (even though we try to purify, end up sometimes with a little contamination from the organism in your product |
| This is a G-CSF that we’re biologically producing in YEASTS, but once we’ve harvested that protein, its pegylated—> increasing the 1/2 life, same MOA as Filgrastim in finding the same receptor, stimulating the neutrophil counts and kinetics are different compared to Filgrasti because of the pegylation; *medication is NOT cleared by glomerular filtration which is usually how Filgrastin is cleared. *neutrophil-mediated clearance of this drug (**SELF-REGULATING) | Pegfilgrastim *CHECK WITH SMITH**** |
| Pegfilgrastim drug info from slide? | - Pegylated recombinant human G-CSF; Generated by conjugation of 20,000-dalton polyethylene glycol to N- terminal methyionyl reside of G-CSF MOA: Same as Filgrastim PK: Clearance by glomerular filtration is minimized therefore longer t1/2 than filgrastim; Studies suggest neutrophil-mediated clearance may be self- regulating **** ⭐️ AE: Same as Filgrastim |
| These 2 G-CSFs are biosimilar products—> | Efbemalenograstim Alfa-vuxw and Eflapegrastim-xnst |
| MOA of Efbemalenograstim Alfa-vuxw and Eflapegrastim-xnst? Indication? Administration? | MOA: a recombinant human G-CSFs Indication: • to decrease the incidence of infection manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia Admin: SQ once per chemotherapy cycle given approx. 24hr after cytotoxic chemotherapy |
| Adverse reactions of Efbemalenograstim Alfa-vuxw and Eflapegrastim-xnst? | Efbemalenograstim alfa-vuxw: Most common adverse reactions (≥10%) were nausea, anemia, and thrombocytopenia (monitor close) • Eflapegrastim-xnst: The most common adverse reactions (≥20%) are fatigue, nausea, diarrhea, bone pain, headache, pyrexia, anemia, rash, myalgia, arthralgia, and back pain |
| Efbemalenograstim Alfa-vuxw and Eflapengrastim-xnst-> both of these drugs are _____ ________ | Fusion proteins; G-CSFs *that may also be expressed in E. Coli (have a produced protein and they’re attaching it to the heavy chain of an antibody, so the FC chain (gives it more structure so its not easily cleared as rapidly from the body |
| Smith: Efbemalenograstim Alfa-vuxw is a ____ ____ protein. Eflapegrastim-xnst is actually ________ so it has a fusion protein that has a longer 1/2 life *both of these have a longer 1/2 life than other G-CSF products so given once per chemocycle. | pure fusion protein (fused to the antibody; pegylated |
| This biological is a Cyclin dependent kinase (CDK) 4/6 inhibitor: _________. Remember the cell cycle from first lecture** cells will express “tools” to bump itself through different phases of the cell cycle. We learned by CDK4/6 get expressed in the G1 phase and their presence pushes the cell from G1 to S phase (normal part of cell division). CDKs or cyclins may be over expressed or hyperactive 4/6 could drive cells from G1 to S phase too rapidly leading to a cell dividing out of control. | Trilaciclib; *so you prevent the cell from being pushed from the G1 to the S phase |
| SMITH Concept to understand: Figure of cell with receptors for ligands that stimulate normal cells to divide (growth factors, etc) Growth factor stimulates down to the ______ to get the cell to start dividing and will see a lot of times, the growth factors are signaling the expression of _______ | cyclins *i.e. Cyclin D—> will be increased and that will activate more of the CDK 4/6. *CDK inhibitors are acting on CDK4 or6 in the NUCLEUS when they have been activated by Cyclin D. |
| Cyclin dependent kinase (CDK) inhibitors figure showing how the cyclins and CDKs work to get the cells to move from the G1 to the S phase. 1. TF: E2F? *not allowed to be working all the time, should only be working when the cell is supposed to divide. 2. What prevents E2F from kicking the cell to the S phase? 3. When do we get E2F free to make the machinery? 4. CDK inhibitors? | 1. When E2F is allowed to do its job, this is the TF that’s causing the genes to be expressed that do the driving of the cell from G1 to S phase. 2. Protein called Retinoblastoma protein (pRB). 3. There are other signals (pro-mitotic signals) expressed at appropriate times—> that’s when we get cyclin D expression increased that activates the CDKs and CDKs phosphorylates the pRP that releases E2F. 4. Stop the CDK and results in teh inability of E2F to be released |
| Trilaciclib is our CDK4/6 inhibitor. Indication? MOA? | Indication: Indication: decreases chemotherapy-induced myelosuppression in patients on certain chemotherapy regimens MOA: – transiently maintains immune cells, hematopoietic stem and progenitor cells in G1 cell cycle arrest – When held in G1, cells won’t be dividing and therefore not targeted by the chemotherapy, reducing bone marrow toxicity – t1/2 is approximately 14 h; bone marrow cell cycle arrest lasts for up to 32 h after a single dose – Then bone marrow progenitor subsets resume proliferation |
| How is Trilaciclib administered? | single IV 30-min infusion w/in 4hr prior to chemotherapy on each day of chemotherapy; *we use it b/c we’re going to pause a lot of those hematopoetic stem cells in the G1 cycle (arrest); holds the cells in G0 and they are not replicating; arrest last for 32 hr and once the chemo dose is given and cleared, then Trilaciclib will be cleared, and those bone marrow cells will then get released from their hold in G1 and start going back through into the rest of the cell cycle. |
| We are using Trilaciclib to try to prevent a lot of the bone marrow suppression that occurs when we use other chemo agents and this is especially useful when pts have become ________ | neutropenic *we use Trilaciclib, try to hold those immature WBC in the G1 phase, let the chemo go through, kill off the cancer cells, and then these WBC precursors will be released and go on to the S-phase once Trilaciclib has been cleared |
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Xander635
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