Pharmacotherapy Vi - Chemotherapy Induced Myelosuppresion

Front 1

Describe the pharmacology of Colony-stimulating Factor

Back 1

Pluripotent Hemopoietic stem cells differentiate into Lymphoid Progenitor cells (NK, T, B cells) and Myeloid Progenitor Cells.

Myeloid Progenitor Cells, using GM-CSF and other cytokines differentiate into:
Erythroid Progenitor Cells
Megakaryocytes
Basophil Progenitor Cells
Eosinophil Progenitor Cells
Granulocyte-monocyte Progenitor Cells

Front 2

Continuation

Back 2

Erythroid Progenitor Cells (Turn into Erythrocytes via Erythropoietin)
Megakaryocytes (Bud off Platelets via thrombopoeitin
Basophil Progenitor Cells (Turn into Basophils)
Eosinophil Progenitor Cells (Turn into Eosinophils)
Granulocyte-monocyte Progenitor Cells (Turn into Neutrophils via G-CSF and Monocytes via M-CSF)
So, G-CSF has more narrow effects than GM-CSF

Front 3

Continuation

Back 3

CSF's increase Neutrophil Production, Maturation, Activation and Migration

Administration of CSF increases Neutrophil counts, decrease trough Neutrophil counts during chemotherapy in comparison to no CSF administered.

Front 4

What are the indications for Primary Prophylaxis use of CSFs

Back 4

If the regimen's risk of febrile neutropenia is > 20%
If the regimen's risk of febrile neutropenia is 10-20% and one of the following:
Age > 65
Pre-existing neutropenia
Poor performance status
Impaired renal or hepatic function
Extensive prior chemotherapy
Poor nutrition
Active Infection

Front 5

Continuation

Back 5

Dose dense therapy when supported by clinical evidence.
Dose dense therapy - a strategy for giving chemotherapy cycle faster than you normally would. Giving stimulating agents may allow this. This is appropriate for certain patients.
CHOP-14 (standard for non-Hodgkin's lymphoma given every 14 days)
CHOP-21

Mobilize Peripheral Blood Stem Cells in preparation of Autologous Stem Cell Transplant (Higher doses)

Front 6

Risk <10 % - not a candidate, but now....
After 3 days of antibiotics, patient is still febrile/neutropenic. Is CSF indicated now?

Back 6

Controversial - risk factors need to be present

Front 7

What are the risk factors that need to be present for this to be indicated?

Back 7

One of these:
Sepsis
Age >65
ANC < 100 or expected length > 10 days
Pneumonia
Invasive fungal infection
Hospitalization at time of fever
Prior episode of FN

Front 8

What options are available for decreasing the risk of FN in the future going forward?

Back 8

Dose reduction
Alternative regimen
Secondary prophylaxis

Front 9

Name the available Growth Factors

Back 9

G-CSF
-Filgastim 5 mcg/kg (round to 300 mcg or 480 mcg vial size) SC daily
- Do not give in period of 24 hours before to 24 hours after chemotherapy

Pegfilgrastim 6 mg SC once
-Pegylation provides prolonged effect due to reduced clearance
- Do not give in period of 14 days before to 24 hr after chemotherapy

Front 10

Why can't you give these agents the day of chemotherapy?

Back 10

Chemotherapy kills rapidly dividing cells.
These agents increase the rate of neutrophil production, so if given concomitantly you will actually do harm to the patient as the chemo will kill the rapidly dividing neutrophils

Front 11

Continuation of available agents

Back 11

GM-CSF
-Sargramostim 250 mg/m^2 SC daily
-Do not give in a period of 24 hours before to 24 hours after chemotherapy

Front 12

How do you select which agent to use?

Back 12

There are few comparative trials

Cost: Filgrastim (G-CSF), Sargramostim (GM-CSF) 200-300 dollars per dose
Pegfilgrastim 2000-3000 per dose

GM-CSF > G-CSF adverse effects

Front 13

What are the adverse effects of these agents?

Back 13

Bone pain
Fever
Diarrhea
Nausea
Rash
Edema
Injection site pain
Effusions

Front 14

When do you stop therapy?

Back 14

Resolution of Neutropenia
ANC > 10,000
ANC > 1000 x 3 days
whichever comes first

Front 15

Overview of chemotherapy induced anemia.
This is controversial. Guidelines aren't clear. In mild malignancies this is controversial.

Back 15

Anemia occurs in 30-90 percent of cancer patients.
Causes include bleeding, hemolysis, marrow infiltration of tumor
Chemo toxicity to RBC precursors
Chemo induced nephrotoxicity
Symptoms: Fatigue, Syncope, Chest Pain

Front 16

How do you manage anemia?

Back 16

Evaluate iron deficiency (don't have to know ferritin, transferrin sat values)

--> PRBC Transfusion or ESA Administration

Front 17

What are the indications for ESA therapy in cancer patients?

Back 17

Myelodysplastic syndrome

Patients with CIA who are receiving palliative chemotherapy for non-myeloid malignancies (Not recommend for curative disease)
- Treatment period can continue ONLY up to 6 weeks following chemotherapy

Front 18

When a patient is done with chemotherapy and they are still anemic, can they now receive ESA?

Back 18

No, still not a candidate
Only while you are getting chemotherapy.

Front 19

If the patient now has metastatic incurable ovarian cancer? Is she now a candidate?

Back 19

Yes

Front 20

What ESA's are available?

Back 20

Epoetin alfa 40,000 units SC once weekly

Darbepoetin 500 mcg SC every 3 weeks

Front 21

How do you monitor these agents?

Back 21

Cannot start these agents if Hgb > 10!!!
Monitor Hg levels weekly
Initial response requires at least 2 weeks
Reduce dose if Hg increases > 1g/dL in a 2 week period
Increase dose if no response in 4 weeks
Discontinue when Hg reaches goal of avoiding transfusions, or no response after 8 weeks

Transfusion is your treatment in acute situations. These agents take a while to work.

Front 22

What are the adverse effects of these agents?

Back 22

Decreases survival (mostly when Hg > 12 g/dL)
Increased thrombosis
Time to tumor progression shortened
Hypertension
Seizures
ESA neutralizing antibodies (causing pure red cell aplasia - mostly in europe with a different formulation but has happened here)

Front 23

Summary graph

Back 23

Shows that targeting Hg > 12 there are bad outcomes. Patients died faster.

Front 24

What are the benefits?

Back 24

Transfusion avoidance
-Transfusion reactions, viral transmission, iron overload, thrombotic events

Front 25

What is REMS?

Back 25

Risk Evaluation and Mitigation Strategy
REMS program for these agents is called ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs)
Provider must go online, complete training program, and then each patient must be counseled on the risk and benefits of ESAs and an acknowledgement form must be signed.

Front 26

Fact:

Back 26

Medicare only covers this if Hg < 10 g/dL prior to any dose.
All the guidelines say over 10 is okay, but it won't be paid for.