Pharmacological Treatment of Anemia - KMS

Question 1

How much elemental Fe is absorbed each day from diet?

Answer 1

0.5-1 mg absorbed/day from 10-15 mg elemental iron in the average diet

Question 2

Where is Fe absorbed in the GI tract?

Answer 2

primarily in the duodenum and proximal jejunum

Question 3

How can Fe absorption in the GI tract increase?

Answer 3

Increases in response to low iron stores or increased iron requirements

Question 4

What form of Fe can be absorbed completely and without change to it?

Answer 4

Heme iron in hemoglobin and myoglobin

can be absorbed intact without first having to be dissociated into elemental iron (e.g., iron in meat protein)

Question 5

Heme Fe can be absorbed intact, but how is nonheme Fe absorbed?

Answer 5

Nonheme iron must be reduced by ferroreductase to ferrous iron (Fe²⁺) before absorption can occur

Question 6

What happens to absorbed Fe when Fe stores are high, or requirements are low?

Answer 6

When iron stores are high and/or iron requirements are low,

absorbed iron is diverted into ferritin in the intestinal epithelial mucosal cells for storage

Question 7

What happens to absorbed Fe when stores are low or requirements are high?

Answer 7

When iron stores are low and/or iron requirements are high,

absorbed iron is immediately transported from the mucosal cells to the bone marrow to support hemoglobin production

Question 8

What transports Fe in plasma?

Answer 8

Transferrin

– a β-globulin that binds two molecules of ferric iron (Fe³⁺) and transports iron in the plasma

Question 9

Fe is shuttled around by transferrin, but how does it get into RBCs?

Answer 9

The transferrin-iron complex enters maturing erythroid cells by binding to integral membrane glycoprotein receptors (transferrin receptors) and undergoing receptor-mediated endocytosis

The ferric iron is released in endosomes, reduced to ferrous iron, transported by the divalent metal transporter (DMT1) into the cell, and enters the hemoglobin synthesis pathway or is stored as ferritin

Question 10

What can increase the number of transferrin receptors on developing erythroid cells?

Answer 10

Increased erythropoiesis

Question 11

What is associated with an increased conc. of serum transferrin?

Answer 11

Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin

Question 12

What form is iron stored as? Where?

Answer 12

almost always stored as ferritin (ferritin is the complex of iron and apo-ferritin, a transferrin-like protein that binds ferrous iron for storage)

stored in intestinal mucosal cells, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells

Question 13

How do levels of free Fe change Fe storage?

Answer 13

Low levels of free iron inhibit apoferritin synthesis and shifts the balance of iron binding toward transferrin

High levels of free iron stimulate production of apoferritin to reduce iron toxicity

Question 14

How is Fe eliminated?

Answer 14

There is no specific mechanism for iron excretion

Iron balance is achieved by changing intestinal absorption and storage of iron in response to the body’s needs

Question 15

What is the clinical indication for Fe preparations?

Answer 15

The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia

Question 16

What type of Fe salts should be used for oral Fe therapy?

Answer 16

Only ferrous salts should be used because ferrous iron is most efficiently absorbed

(e.g., ferrous sulfate, ferrous gluconate, ferrous fumarate)

Question 17

How much oral Fe is absorbed?

Answer 17

Roughly 25% of oral iron given as ferrous salt can be absorbed

Question 18

How does oral absorption of oral Fe therapy affect dosing? What is the typical dose?

Answer 18

50-100 mg of iron can be incorporated into hemoglobin daily in an iron-deficient individual; 200-400 mg iron/day is a typical dose

Question 19

How should oral iron therapy be taken?

Answer 19

Should be taken with water or juice on an empty stomach; may be administered with food to prevent irritation

Question 20

What are some ADRs with PO Fe therapy?

Answer 20

Adverse effects include

nausea,

epigastric discomfort,

abdominal cramps,

constipation,

black stools, and

diarrhea (dose related; reduced if taken with or immediately after meals)

Question 21

How can GI discomfort be reduced with PO Fe therapy?

Answer 21

Switching to a different ferrous salt preparation may reduce GI discomfort

Question 22

Who is a candidate for parenteral Fe therapy?

Answer 22

Reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron

and for patients with extensive chronic anemia who cannot be maintained with oral iron alone

(e.g., patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin, small bowel resection, inflammatory bowel disease involving the proximal small bowel, or malabsorption syndromes)

Question 23

How are parenteral forms of Fe formulated?

Answer 23

All parenteral forms of iron are formulated as colloid containing particles with a core of iron oxyhydroxide surrounded by a core of carbohydrate

so that iron is released slowly from the stable colloid particle after infusion

(avoids the severe toxicity of free ferric iron upon administration)

Question 24

Why is parenteral administration of Fe favored sometimes?

Answer 24

bypasses iron storage regulatory mechanisms of the intestine and can deliver more iron than can safely be stored;

monitoring iron storage levels helps to avoid serious toxicity of iron overload

Question 25

What are the 3 forms of parenteral Fe available in the US?

Answer 25

Iron dextran

Sodium ferric gluconate complex

Iron sucrose complex

Question 26

How is Fe dextran administered? Which way is most common?

Answer 26

May be administered by deep IM injection or by IV infusion (most common because it eliminates local pain and tissue staining that occurs with IM injections and can administer a higher dose in comparison to IM)

Question 27

What are the ADRs associated with Fe dextran? What should you try before administering it?

Answer 27

Adverse effects include headache, light-headedness, fever, arthralgias, nausea, vomiting, back pain, flushing, urticaria, bronchospasm, and anaphylaxis and death (rare)

A small test dose should always be given due to hypersensitivity reactions

Question 28

How is Na Fe+++ gluconate complex administered?

Answer 28

Only administered IV

Less likely to cause hypersensitivity reactions

Question 29

How is Fe sucrose complex administered?

Answer 29

IV only

Question 30

Which 2 parenteral Fe therapies are less likely to cause hypersensitivity reactions?

Answer 30

Sodium ferric gluconate complex

Iron sucrose complex

Question 31

What population is acute Fe toxicity seen in?

Answer 31

almost exclusively in young children who accidentally ingest iron tablets

(as few as 10 tablets of common iron preparations can be lethal)

Question 32

What are the symptoms of acute Fe toxicity?

Answer 32

necrotizing gastroenteritis,

accompanied by vomiting and abdominal pain,

and bloody diarrhea

followed by shock, lethargy, and dyspnea

Question 33

What can acute Fe toxicity ultimately result in?

Answer 33

Improvement may be noted and followed by:

severe metabolic acidosis, coma, and death

Question 34

How can acute Fe toxicity be treated? What common poisoning treatment is ineffective?

Answer 34

Urgent treatment includes whole bowel irrigation and parenteral deferoxamine (potent iron-chelating compound that promotes excretion in feces and urine)

Activated charcoal does not bind iron and is ineffective

Question 35

What is another name for chronic Fe toxicity?

Answer 35

hemochromatosis

Question 36

Where can excess Fe deposits cause major damage? What can this lead to?

Answer 36

Excess iron deposits in the heart, liver, pancreas, and other organs can lead to organ failure and death

Question 37

In what population of patients is hemochromatosis most common?

Answer 37

Toxicity is most common in patients with:

inherited hemochromatosis, (a disorder characterized by excessive iron absorption)

and in patients who receive many red cell transfusions over a long period of time

Question 38

How is chronic Fe toxicity treated?

Answer 38

Efficiently treated with intermittent phlebotomy

(deferoxamine is less efficient and potentially hazardous but may be only option for iron overload unsuccessfully managed by phlebotomy)

Question 39

What can reduce liver Fe concentrations?

Answer 39

Oral iron chelator deferasirox reduces liver iron concentrations

but data in removing iron from heart is lacking

Question 40

What can cobalamin deficiency lead to?

Answer 40

1. VITAMIN B₁₂ (COBALAMIN)

Essential cofactor in humans; deficiency can lead to megaloblastic anemia, gastrointestinal symptoms, and neurologic abnormalities

Question 41

What are the sources of B12?

Answer 41

common dietary sources are meat, eggs, and dairy products

Vitamin B12 is naturally synthesized by microorganisms, but humans are incapable of doing so and must obtain vitamin B12 in their diet

Porphyrin-like ring with a central cobalt atom attached to a nucleotide

Question 42

What are the active forms of cobalamin in humans?

Answer 42

Cyanocobalamin (synthetic), hydroxocobalamin, and other cobalamins found in food sources are converted to

deoxyadenosylcobalamin and methylcobalamin, the active forms in humans

Question 43

What forms of cobalamin are available for clinical use?

Answer 43

Both cyanocobalamin and hydroxocobalamin are available for clinical use

Question 44

How much cobalamin is absorbed daily, and where is it stored?

Answer 44

Average diet in the USA contains 5-30 mcg/day; 1-5 mcg vitamin B₁₂ is typically absorbed; daily requirement is approximately 2 mcg

Stored primarily in the liver (3000-5000 mcg total); only trace amounts are lost in the urine and stool

Question 45

If someone were to take in no more vitamin B12, what ill effects would they see and when?

Answer 45

Due to the amount of B₁₂ stored and low daily requirement, if B₁₂ absorption stopped completely it would take about 5 years to develop megaloblastic anemia

Question 46

What is essential to the absorption of vitamin B12?

Answer 46

B­₁₂ is only absorbed after complexing with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa (absorption occurs in the distal ileum by a highly selective receptor-mediated transport system)

Question 47

What is a B12 deficiency often a result of?

Answer 47

B₁₂ deficiency most often results from malabsorption due to lack of intrinsic factor or to loss or malfunction of the absorptive mechanism in the distal ileum; nutritional deficiency is rare but may be seen in strict vegetarians after many years

Question 48

How is B12 transported after absorption?

Answer 48

B12 is transported by the glycoproteins transcobalamin I, II, and III

(excess is transported to the liver for storage)

Question 49

What 2 essential enzymatic rxns in humans require B12?

Answer 49

synthesis of the amino acid methionine and the synthesis of succinyl-CoA

Question 50

The synthesis of methionine requires vitamin B12. What is another product that gets made during this reaction?

Answer 50

tetrahydrofolate

Question 51

How are B12 and folate deficiency linked?

Answer 51

B12 deficiency causes the accumulation of N5-methyltetrahydrofolate (Tetrahydrofolate precursor) and depletion of tetrahydrofolate

(link between B12 and folic acid metabolism; B12 deficiency can be partially corrected by ingestion of large amounts of folic acid, which largely corrects the anemia caused by B12 deficiency; folic acid does not prevent neurologic manifestations of B12 deficiency, which are thought to be caused by loss of methionine synthesis

Question 52

In addition to tetrahydrofolate deficiency, what else can B12 deficiency cause?

Answer 52

B₁₂ deficiency causes the accumulation of homocysteine due to the reduced formation of methylcobalamin

Question 53

How can B12 deficiency be measured?

Answer 53

In patients deficient in B₁₂, methylmalonic acid and methylmalonyl-CoA accumulate (serum and urine levels of methylmalonic acid are diagnostic for B₁₂ deficiency)

B12 deficiency causes the accumulation of homocysteine due to the reduced formation of methylcobalamin; increased serum levels are diagnostic of B12 deficiency

Question 54

What are some common causes of B12 deficiency?

Answer 54

pernicious anemia,

partial or total gastrectomy,

and conditions that affect the distal ileum (e.g., malabsorption syndromes, inflammatory bowel disease, small bowel resection)

Question 55

What are the most common characteristic clinical manifestations of B12 deficiency?

Answer 55

megaloblastic, macrocytic anemia, often with associated mild or moderate leukopenia or thrombocytopenia (or both),

and a characteristic hypercellular bone marrow with an accumulation of megaloblastic erythroid and other precursor cells

Question 56

What is the neurologic syndrome associated with vitamin B12 deficiency?

Answer 56

deficiency usually begins with paresthesias in peripheral nerves and weakness; it progresses to spasticity, ataxia, and other CNS dysfunctions (B12 treatment stops the progression of neurologic disease but may not fully reverse neurologic symptoms)

Question 57

What are almost all cases of B12 deficiency caused by? How does this affect therapy/treatment?

Answer 57

Almost all cases of B₁₂ deficiency are due to malabsorption; therefore, parenteral injections are required for therapy (often lifelong if syndrome causing deficiency is incurable)

Question 58

What forms of B12 are available for parenteral injections?

Answer 58

cyanocobalamin and hydroxocobalamin forms of B₁₂

Question 59

What is the dosing for B12 therapy?

Answer 59

Initial therapy: 100-1000 mcg B₁₂ IM daily or every other day for 1-2 weeks to replenish body stores

Maintenance therapy: 100-1000 mcg B₁₂ IM once a month for life

Question 60

What is the dosing for B12 deficiency if neurological symptoms are present?

Answer 60

If neurologic abnormalities are present, maintenance therapy should be given every 1-2 weeks for 6 months before switching to monthly injections

Maintenance therapy: 100-1000 mcg B₁₂ IM once a month for life

Question 61

What administration of B12 is an acceptable alternative to injections?

Answer 61

Oral and intranasal administration of B₁₂ are usually sufficient to treat patients with pernicious anemia who refuse or cannot tolerate injections

Question 62

What is folic acid required for?

Answer 62

Required for synthesis of amino acids, purines, and DNA

Question 63

What is the major consequence of folic acid deficiency? What else does it play a role in?

Answer 63

Major consequence of deficiency is anemia;

folic acid deficiency is implicated as a cause of congenital malformations in newborns and

may play a role in vascular disease

Question 64

How much folic acid is absorbed daily? How much is stored?

Answer 64

Average US diet contains 500-700 mcg of folates daily;

50-200 mcg are absorbed in the typical individual (300-400 mcg absorbed daily in pregnant women);

5-20 mg folates are stored in the liver and other tissues

Question 65

What are the richest dietary sources of folic acid?

Answer 65

yeast, liver, kidney, and green vegetables

Question 66

How are folates excreted? How quickly can serum levels fall?

Answer 66

Folates are excreted in the urine and stool and destroyed by catabolism; serum levels fall within a few days when intake is diminished

Question 67

What can develop after intake of folic acid stops?

Answer 67

Due to relatively low body stores and high daily requirements, folic acid deficiency and megaloblastic anemia may develop within 1-6 months after the intake of folic acid stops

Question 68

Where is folic acid absorbed?

Answer 68

Unaltered folic acid is absorbed in the proximal jejunum

Question 69

What form does dietary folates consist of? What must happen to it before it is changed to tetrahydrofolate?

Answer 69

Dietary folates consist primarily of polyglutamate forms of N⁵-methyltetrahydrofolate; all but one glutamyl residue of the polyglutamates must be hydrolyzed by the enzyme α-1-glutamyl transferase within the brush border of the intestinal mucosa before absorption

Once inside cells, N5-methyltetrahydrofolate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12

Question 70

What pathways is tetrahydrofolate important in, and why?

Answer 70

Tetrahydrofolate cofactors participate in one-carbon transfer reactions, which are essential components of synthesis pathways of amino acids, purines, and DNA

Question 71

Why is tetrahydrofolate important in antineoplastic agents?

Answer 71

Considerable amounts of tetrahydrofolate are consumed by rapidly proliferating tissues;

enzymes in the dTMP cycle are the targets of two antineoplastic agents (methotrexate inhibits dihydrofolate reductase and 5-fluorouracil inhibits thymidylate synthase)

Question 72

What does folic acid deficiency result in?

Answer 72

Folic acid deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B₁₂ deficiency

Question 73

How is megaloblastic anemia as a result of folic acid defiency versus B12 deficiency differentiated?

Answer 73

Folate deficiency does not cause the neurologic syndrome seen in B₁₂ deficiency (folic acid therapy in B₁₂ deficiency has no effect on neurologic symptoms)

Question 74

What often causes folic acid deficiency?

Answer 74

Deficiency is often caused by inadequate dietary intake of folates

(e.g., alcoholics with poor diet and diminished hepatic storage,

pregnant women and

patients with hemolytic anemia with increased folate requirements,

patients with malaborption syndromes,

patients undergoing renal dialysis have folates removed from plasma)

Question 75

What are some drugs that can cause folic acid deficiency?

Answer 75

methotrexate, trimethoprim, and pyrimethamine (all inhibit dihydrofolate reductase) and long-term therapy with phenytoin

Question 76

How much folic acid is sufficient to reverse megaloblastic anemia?

Answer 76

1 mg/day PO folic acid is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores in almost all patients (even in patients with malaborption issues)

Question 77

What patients should receive folic acid supplementation?

Answer 77

high-risk patients

alcoholics with poor diet and diminished hepatic storage,

pregnant women and

patients with hemolytic anemia with increased folate requirements,

patients with malaborption syndromes,

patients undergoing renal dialysis have folates removed from plasma

Question 78

What type of products are hematopoietic growth factors? What is their general purpose?

Answer 78

glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in bone marrow

Question 79

What do hematopoietic growth factors treat?

Answer 79

Hematopoietic agents and drugs that mimic their action are used to treat various conditions, such as anemia and cancer (patients may require treatment for neutropenia, thrombocytopenia, and stem cell transplantation)

Question 80

Where is erythropoietin normally expressed?

Answer 80

peritubular interstitial cells of the kidney

Question 81

What does EPO (erythropoietin) bind to cause an effect?

Answer 81

Binds to a receptor on the surface of committed erythroid progenitors in the marrow after secretion

(erythropoietin receptors are members of the cytokine receptor superfamily and initiate the JAK/STAT signal transduction pathway (kinase signaling cascade))

Question 82

What can rapidly cause EPO levels to rise? What is the result?

Answer 82

With anemia or hypoxemia, synthesis rapidly increases by 100-fold or more, serum erythropoietin levels rise, and marrow progenitor cell survival, proliferation, and maturation are stimulated

(can be disrupted by kidney disease, marrow damage, or a deficiency in iron or an essential vitamin)

Question 83

What can disrupt EPO secretion?

Answer 83

Inflammatory cytokines, released due to an infection or an inflammatory state, suppress erythropoietin secretion, iron delivery, and progenitor proliferation (inflammation also affects iron metabolism)

Question 84

What are the names for recombinant human erythropoietin products?

Answer 84

rHuEPO, epoetin alpha

Question 85

How is epoetin alpha made? ROA?

Answer 85

Produced in a mammalian cell expression system for IV administration

Question 86

How is epotein alpha dosed?

Answer 86

Half-life 4-8 hours but effects on marrow progenitors lasts much longer, allowing for once-weekly dosing to produce an adequate response

Administered 3x/week in patients with chronic renal failure (not cleared by dialysis)

Question 87

What is darbepoetin alpha? Methoxy polyethylene glycol-epoetin beta?

Answer 87

a type of recombinant human erythropoietin

modified form that is more glycosylated and has a half-life of 24-26 hours

Methoxy polyethylene glycol-epoetin beta: long-acting isoform administered 1-2x/month

Question 88

What is the MOA of recombinant EPO?

Answer 88

MOA: induces erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells;

induces the release of reticulocytes from the bone marrow into the bloodstream, where they mature to erythrocytes (agonist at erythropoietin receptors on red cell progenitors)

Question 89

What is the ultimate result of recombinant EPO therapy?

Answer 89

Results in an increase in reticulocyte counts (10 days) followed by a rise in hematocrit and hemoglobin levels (2-6 weeks)

Question 90

How are recombinant EPO agents used clinically? In combination with what drugs?

Answer 90

Erythropoiesis-stimulating agents (ESAs) are used to decrease the need for RBC transfusions in patients with anemia secondary to chronic kidney disease (endogenous erythropoietin levels are low because the kidneys cannot produce the growth factor)

Nearly always coupled with oral or parenteral iron supplementation (and sometimes folate supplementation) in patients with chronic kidney disease

Question 91

In addition to eryropoiesis in chronic kidney disease, what are 3 other indications for recombinant EPO?

Answer 91

Treatment of anemia due to concurrent myelosuppressive chemotherapy in patients with cancer (nonmyeloid malignancies) receiving chemotherapy (palliative intent) for a planned minimum of 2 additional months of chemotherapy

Treatment of anemia associated with HIV (zidovudine) therapy when endogenous erythropoietin levels ≤ 500 mUnits/mL

Reduction of allogenic RBC transfusion for elective, noncardiac, nonvascular surgery when perioperative Hgb is 10-13 g/dL and there is a high risk for blood loss

Question 92

What conditions are erythropoiesis stimulating agents (ESAs) not indicated for?

Answer 92

(1) Cancer patients receiving hormonal therapy, therapeutic biologic products, or radiation therapy unless also receiving concurrent myelosuppressive chemotherapy
(2) Cancer patients receiving myelosuppressive chemotherapy when the expected outcome is curative
(3) Surgery patients who are willing to donate autologous blood
(4) Surgery patients undergoing cardiac or vascular surgery
(5) As a substitute for RBC transfusion in patients requiring immediate correction of anemia

Question 93

What is an off-label use for ESAs?

Answer 93

treatment of symptomatic anemia in myelodysplastic syndrome (MDS)

Question 94

Are ESAs considered a performance enhancing drug?

Answer 94

yes - Banned by the International Olympic Committee

Question 95

What are the most common ADRs with ESAs?

Answer 95

Most common adverse effects are hypertension and thrombotic complications (may require increased anticoagulation);

aggressive use in patients with chronic renal failure or cancer has been linked to increased mortality and CV events, reduce risk by using lowest dose needed

Allergic reactions are uncommon

Question 96

What patients are ESAs contraindicated?

Answer 96

Contraindicated in patients with uncontrolled hypertension

Question 97

What are the 2 categories of myeloid growth factors?

Answer 97

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are two myeloid growth factors currently available for clinical use

Question 98

What are the 3 myeloid growth factors for right now?

Answer 98

Filgrastim (rHuG-CSF)

Pegfilgrastim

Sargramostim (rHuGM-CSF)

Question 99

What is filgrastim? How is it made?

Answer 99

Recombinant human G-CSF produced in a bacterial expression system

Nonglycosylated peptide of 175 amino acids

Question 100

What is the half life of filgrastim? ROA?

Answer 100

Serum half-life approximately 3.5 hours after IV or subcutaneous administration

Question 101

What is pegfilgrastim?

Answer 101

Covalent conjugation product of filgrastim and polyethylene glycol (PEG)

Question 102

What is the half life of pegfilgrastim? MOA?

Answer 102

1. Longer serum half-life than filgrastim (15-80 hours)
2. Can be injected once per myelosuppressive chemotherapy cycle instead of daily for several days

Question 103

What is sargramostim?

Answer 103

Recombinant human GM-CSF produced in a yeast expression system

Glycosylated peptide of 127 amino acids

Question 104

What is the half life of sargramostim? ROA?

Answer 104

IV half-life approximately 1 hour; SubQ half-life approximately 3 hours

Question 105

What do myeloid growth factors do? What receptors do they work on?

Answer 105

Myeloid growth factors stimulate proliferation and differentiation of one or more myeloid cell lines and enhance the function of mature granulocytes and monocytes

Receptors for myeloid growth factors are members of the cytokine receptor superfamily and initiate the JAK/STAT signal transduction pathway

Question 106

What are the 3 actions of G-CSF?

Answer 106

1. Stimulates proliferation and differentiation of progenitors already committed to the neutrophil lineage
2. Activates the phagocytic activity of mature neutrophils and prolongs survival
3. Increases concentration of hematopoietic stem cells in peripheral blood (major advance in transplantation because peripheral blood stem cells (PBSCs) may be used rather than bone marrow stem cells)

Question 107

How does GM-CSF differ from G-CSF?

Answer 107

Broader biologic actions than G-CSF

Primary therapeutic effect is to stimulate myelopoiesis

Question 108

What are the 4 actions of GM-CSF?

Answer 108

1. Stimulates the proliferation and differentiation of early and late granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors
2. Stimulates the function of mature neutrophils
3. Stimulates T-cell proliferation together with interleukin-2
4. Increases concentration of peripheral blood stem cells to a lesser extent than G-CSF

Question 109

How can G-CSF help cancer chemotherapy-induced neutropenia?

Answer 109

G-CSF has been shown to dramatically accelerate the rate of neutrophil recovery after dose-intensive myelosuppressive chemotherapy, reduce the duration of neutropenia, and raise the nadir count (low-point of neutrophil count) following a cycle of chemotherapy

Clinical trials have shown that G-CSF reduces episodes of febrile neutropenia, requirements for broad-spectrum antibiotics, infections, and days of hospitalization, but have not shown improved survival in cancer patients

Question 110

How is administration of pegfilgrastim different from filgrastim in treatment for cancer chemotherapy-induced neutropenia?

Answer 110

Pegfilgrastim may be administered less frequently and may shorten the period of severe neutropenia in comparison to filgrastim; sargramostim may also be used

Question 111

What is not an ADR associated with myeloid growth factors, according to the DSA?

Answer 111

No evidence that myeloid growth factors reduce the rate of remission or increase relapse rate in patients with myeloid or lymphoblastic leukemia (concern based on the fact that leukemic cells arise from progenitors regulated by HGFs including G-CSF and GM-CSF)*

*Actually controversial to untrue, check UpToDate, but know this for the test

Question 112

In addition to cancer chemotherapy-induced neutropenia, what are some other applications for myeloid growth factors?

Answer 112

1. Treatment of neutropenia associated with congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia
2. May be combined with other growth factors for treatment of pancytopenia
3. Autologous stem cell transplantation in patients undergoing high-dose chemotherapy
   
   1. Mobilizes PBSCs for collection by leukapheresis prior to chemotherapy
4. Reduces time to engraftment and to recovery from neutropenia after chemotherapy and reinfusion of PBSCs (or bone marrow stem cells)

Question 113

What are megakaryocyte growth factors indicated for?

Answer 113

Patients with thrombocytopenia have a high risk of hemorrhage

Question 114

What are endogenous regulators of platelet production?

Answer 114

Thrombopoietin and interleukin-11 (IL-11) are endogenous regulators of platelet production

Question 115

Does recombinant thrombopoietin exist?

Answer 115

No - recombinant thrombopoietin cannot be used clinically due to production of autoantibodies that result in development of thrombocytopenia

Question 116

What is oprelvekin? How is it made?

Answer 116

Oprelvekin is the recombinant form of IL- 11 approved for clinical use; produced by expression in Escherichia coli

Question 117

What is the half life and ROA for oprelvekin?

Answer 117

Half-life is 7-8 hours when injected SubQ

Question 118

What is the MOA for oprelvekin?

Answer 118

activates specific cell surface cytokine receptors to stimulate the growth of multiple lymphoid and myeloid cells;

acts synergistically with other growth factors to stimulate the growth of primitive megakaryocytic progenitors;

increases the number of peripheral platelets and neutrophils

Question 119

What is romiplostim?

Answer 119

peptide agonist of the thrombopoietin receptor, Mpl

Member of a new class of therapeutics called peptibodies, which are peptides with key biologic activities covalently linked to antibody fragments that serve to extend the peptide’s half-life

Question 120

What is the MOA for romiplostim?

Answer 120

MOA: activates Mpl thrombopoietin receptor to cause a dose-dependent increase in platelet count that begins 5 days after SubQ injection and peaks at 12-15 days

Question 121

What is the half life and ROA for romiplostim?

Answer 121

Half-life is 3-4 days after SubQ injection;

half-life is inversely related to serum platelet count

Question 122

What is IL-11 approved for?

Answer 122

IL-11 is approved for the secondary prevention of thrombocytopenia in patients receiving cytotoxic chemotherapy for nonmyeloid cancers; reduces the number of platelet transfusions

Question 123

What is romiplostim approved for?

Answer 123

Romiplostim is approved for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia purpura (ITP) who have had insufficient response to corticosteroids, immune globulin, or splenectomy

Question 124

What are the toxicities associated with IL-11?

Answer 124

Fatigue, headache, dizziness, and cardiovascular effects (e.g., anemia, dyspnea, transient atrial arrhythmias) are the most common

Hypokalemia

All adverse effects are reversible

Question 125

What are the toxicities associated with romiplostim?

Answer 125

Well tolerated except for a mild headache on the day of administration