NEUTROPENIA AND ANEMIA OF
CANCER PATIENTS
477 PHCL
JAMILAH ALSAIDAN MSC
TREATMENT-INDUCED MYELOSUPPRESSION
• To assist patients in recovering from some of the hematologic toxicities of cancer chemotherapy,
several proteins have been developed that stimulate various steps of hematopoiesis; they are
designated as growth factors or stimulatory cytokines.
• These proteins are produced in vivo and bind to specific cell receptors to stimulate stem cell
proliferation and differentiation.
• Hematopoiesis proceeds from a pluripotent stem cell (one that can differentiate in to any of the
hematopoietic cell-lines) in an orderly, timed fashion to mature cells
HEMATOPOIESIS
Image taken from: http://hematologyoutlines.com/atlas
TREATMENT INDUCED NEUTROPENIA
• TREATMENT INDUCED NEUTROPENIA many chemotherapy agents can have toxic effects on the
bone marrow. An infection resulting from chemotherapy-induced neutropenia (CIN) is the primary
life-threatening event of any chemotherapy course.
• Patients experience severe CIN when the absolute neutrophil count (ANC) falls below 500 per µL
• At this time, patients are most vulnerable to bacterial, fungal, and viral infections.
TREATMENT INDUCED NEUTROPENIA
• TREATMENT GOALS:
• prevent prolonged duration of CIN and its associated infection risk by administering primary and
secondary prophylactic myelopoietic cytokines with :
• standard-dose chemotherapy
• and high-dose cytotoxic therapy associated with bone marrow transplantation (BMT).
TREATMENT INDUCED NEUTROPENIA
Introduction
• Chemotherapy- induced neutropenic infections are the primary lifethreatening event of any chemotherapy course. The duration and
severity of CIN are the most important predictors of infection risk.
TREATMENT INDUCED NEUTROPENIA
Introduction
• Myelopoietic growth factors decrease the following:
• the time that granulocyte counts remain below 500per µL,
• the incidence of febrile neutropenia,
• the number of infectious complications in patients receiving high- dose autologous
BMT or allogeneic BMT.
Growth Factors are also effective for mobilizing progenitor cells into the peripheral
blood so that they can be harvested for autologous or allogeneic transplantation.
TREATMENT INDUCED NEUTROPENIA
Management
• WHITE BLOOD CELL GROWTH FACTORS:
• There are three exogenous growth factor agents commonly used for the management of
chemotherapy- induced neutropenia:
• recombinant human granulocyte–macrophage colony stimulating factor (GM-CSF or
Sargramostim),
• Recombinant human granulocyte colony-stimulating factor (G-CSF or Filgrastim),
• A covalent conjugate of rhu-G-CSF and mono-methoxypolyethyleneglycol, commonly referred to
as pegylated G-CSF or Pegfilgrastim.
TREATMENT INDUCED NEUTROPENIA
Management
• Although these agents do not uniformly prevent neutropenia after the administration of
myelosuppressive therapy, they have been found to shorten the duration of neutropenia.
• They are also effective in accelerating neutrophil recovery after BMT and can increase the yield
of peripheral blood stem cells collected by leukophoresis for use in peripheral blood stem cell
transplantation.
TREATMENT INDUCED NEUTROPENIA
Management
• GM-CSF is a127-amino acid glycosylated protein derived from yeast cultures.
• GM-CSF has multi line age effects on granulopoiesis, stimulating both primitive and terminal
differentiation of neutrophils, macrophages, and eosinophils
• G-CSF is a 175-amino acid non glycosylated protein derived from Escherichia coli cultures. Unlike
GM-CSF, the actions of G-CSF are limited to the terminal differentiation of neutrophils.
TREATMENT INDUCED NEUTROPENIA
Management
• Pegylated G-CSF is produced by covalently binding a 20-KD monomethoxypolyethylene glycol
molecule to the N-terminal methionyl residue of filgrastim.
• Its action as a colony-stimulating factor is like that of G-CSF, but Pegyla-on results in reduced renal
clearance and a prolonged persistence in vivo compared with G-CSF
AMERICAN SOCIETY OF CLINICAL ONCOLOGY
(ASCO) GUIDELINES FOR USE OF HGFs
(ASCO)
guidelines
Primary
Prophylactic
Secondary
Prophylactic
PRIMARY PROPHYLACTIC
• Is actually with the first course of chemotherapy)
• Use of CSFS if the expected incidence of febrile neutropenia with a chemotherapy regimen is
40% or greater.
• There are Special circumstances that support CSF use in primary prophylaxis with chemotherapy
regimens for which the incidence of febrile CIN is less than 40%
Special circumstances that support CSF use in primary
prophylaxis with chemotherapy regimens for which the
incidence of febrile CIN is less than 40% are:
• patients receiving dose-intensive
chemotherapy,
• poor performance status(eastern cooperative
oncology group score ≥2),
• age more than 65years,
• advanced cancer (metastatic disease, having
received multiple chemotherapy regimens),
• pre existing neutropenia secondary to disease,
• extensive prior chemotherapy, previous
radiation to the pelvis (as this area contains a
large amount of bone marrow),
• open wounds and active tissue infections,
• decreased immune function (human immuno
deficiency virus infection, acquired
immunodeficiency syndrome, cytopenias,
diabetes mellitus),
Special circumstances that support CSF use in primary
prophylaxis with chemotherapy regimens for which the
incidence of febrile CIN is less than 40% are:
• history of recurrent febrile neutropenia with
previous chemotherapy of similar or lesser
myelosuppressive potential,
• or serum albumin level of 3.5g per dl or less
in patients with non-Hodgkin’s lymphoma or
multiple myeloma
SECONDARYPROPHYLAXIS
• Secondary prophylaxis with CSF is defined as use:
• after a previous febrile CIN episode
• or previous CIN when dose reduction or delay is not appropriate [e.g., Incurable tumors such as
germ cell (testicular) cancers, intermediate / high-grade non-hodgkin’s lymphoma, and hodgkin’s
lymphoma]
• and for patients being treated in the adjuvant or neoadjuvant setting.
• The use of CSFs for the treatment of febrile neutropenia is recommended only if serious prognostic
comorbidities are present.
• Studies have not yet supported a decrease in the number of neutropenic days or duration of
hospitalization beyond antibiotics and/or antifungal therapy alone.
• Serious concomitant illnesses include pneumonia, hypotension, and multi-organ dysfunction.
• There is a mathematical model developed by Silber et al
• The object is to correlate first cycle Absolute Neutrophil Count ANC with a predicted need for CSF
in subsequent chemotherapy dose and maintenance
• Their mathematical model is complex, but soon guidelines using first-cycle nadir counts can be used
to select patients who should receive CSF with subsequent cycles for chemotherapy dose
maintenance.
Test
Result
Flag
Units
Reference Interval
L
103 µL
4.8-10.8
103 µL
130-400
CBC WITH DIFFERENTIAL
White Blood Count
2.0
Platelets
278
Polys
14.8
L
%
43.0-65.0
Polys (absolute)
0.3
L
103 µL
2.2-4.8
Bands (absolute)
0.1
103 µL
TO CALCULATE THE ANC
1. FIND THE WBC, THE POLYS AND BANDS ON THE CBC. WBC 2.0 POLYS 14.8% BANDS 5%
2. ADD THE POLYS AND BANDS.
• (14.8 + 5 = 19.8)
3. MULTIPLY THE SUM OF THE POLYS AND BANDS BY THE WBC.
• 19.8 X 2.0 = 39.6
4. MULTIPLY THE PRODUCT BY 10.
• 39.6 X 10 = 396
THIS PERSON HAS AN ANC OF 396
TO CALCULATE THE ANC
• TO CALCULATE THE ANC FROM ABSOLUTE NUMBERS THE FORMULA IS:
• ABSOLUTE POLYS + ABSOLUTE BANDS MULTIPLIED BY 1000 = ANC
• (0.3 + 0.1) X 1000 = 400
Pharmacokinetics.
absorption and volume of
distribution
distribution
serum halflife SC
serum half-life IV
Dosing frequency
G-CSF
follow firstorder
pharmacokineti
cs
( LINEAR)
is approx.
3.5 hours
is approx. 3.5 hours
daily
GM-CSF
follow firstorder
pharmacokineti
cs
( LINEAR)
162 minutes
( approx. 3
hours)
60minutes
Pegfilgastrim follow firstorder
pharmacokineti
cs
( LINEAR)
15-80 hours
150 ml/kg
Once per chemotherapy
treatment cycle
DOSING.
• After G-CSF use is discontinued the ANC falls rapidly for 1 to 3 days before a new, lower
baseline level is maintained.
• The time to reach a desired ANC with GM-CSF may be 1 day longer, but the ANC levels are
more sustained, with little or no decrease after discontinuation.
DOSING AND ADMINISTRATION
• Filgrastim and sargramostim dosing should begin 24 to 72 hours after chemotherapy and continue
daily past the ANC nadir.
• Pegfilgrastim, in contrast, is administered once per cycle (24 hours after chemotherapy is given in
the cycle) and SHOULD NOT be administered in the period between 14days before and 24 hours
after cytotoxic chemotherapy is administered.
• Administration with in this time period may have the undesired effect of increasing the sensitivity of
rapidly dividing myeloid cells to chemotherapy
DOSING AND ADMINISTRATION
DRUG
Dose
Route and Frequency
GM- CSF ( sargramostim)
250 µg/m2/ day rounded to nearest
50 µg
SC or IV daily
G-CSF ( Filgastrim)
5 µg/kg/ day rounded to the nearest
vial size ( 300 µg or 480µg)
≤70kg = 300µg vial
SC or IV daily
Pegylated G-CSF Pegfilgastrim
6mg fixed dose
SC once per chemotherapy cycle
DOSING AND ADMINISTRATION
• The original recommendations for Filgrastim and sargramostim use were to treat until an ANC
of10,000 per µl was reached, but most clinicians now treat until the ANC is greater than1,500 to
2,500 per µl for 2 consecutive days or for a maximum of 14days.
• Filgrastim and sargramostim should be discontinued at least 24hours before the next
chemotherapy course.
• Discontinuation of the agents 48hours before the next cycle of chemotherapy has also been shown
to decrease the chance of worsening CIN with subsequent cycles.
SIDE EFFECTS
• Body temperature elevation
More common
• local injection site reactions
• bone pain or arthralgias.
• Capillary leak syndrome
Rare
SIDE EFFECTS.
• Particular side effects of the CSFS that should be managed appropriately include temperature
elevation, local injection site reactions, and bone pain or arthralgias.
• Body temperature elevation can occur 30 minutes to 4 hours after injection and usually peaks at
38 ˚C or less. Patients can be given acetaminophen or ibuprofen before injection to prevent this
reaction. If temperature rises above 38.2 ˚C or does not respond to antipyretics, an underlying
infection must be considered.
• Site reactions are typically localized and caused by the injection technique.
SIDE EFFECTS.
• The injection sites should be rotated, and the CSF should be injected at room temperature. It is
often helpful to cool the skin with ice for a few minutes before injection.
• Medullary bone pain and arthralgias are common reactions and can be treated with analgesics.
The pain can be severe but usually resolves 1 to 3 days after CSF use is discontinued.
• Capillary leak syndrome is rarely associatedwiththeyeast-derived gm-csf(sargramostim) product
that is currently available.
PRECAUTIONS
• Administration with combined chemotherapy and radiotherapy has not been studied, and the use
of CSF with daily radiation therapy may worsen neutropenia or damage the bone marrow
• Interaction with lithium!!!!!
PRECAUTIONS
• Lithium results in rapid release of neutrophils as they develop; thus, close monitoring is warranted in
patients receiving concomitant lithium and CSF therapy.
• Lower CSF doses and/or a shorter duration of therapy may be required
• Sargramostim is contraindicated in patients sensitive to yeast-derived products,
• Filgrastim is contraindicated in patients sensitive to E.Coli- derived products.
ANEMIA INDUCED BY ONCOLOGICAL DISEASE
TREATMENT
CAUSES.
• ANEMIA IN PATIENTS WITH CANCER MAY HAVE SEVERAL POTENTIAL CAUSES.
The causes must be differentiated to make
sure that all treatable causes are identified.
CAUSES.
• Cancer may cause anemia directly by :
• Acute or chronic blood loss
• Intratumor bleeding
• Erythrophagocytosis
• Splenomegaly
• Bone marrow replacement
• Cancer may cause anemia by physiologic effects
of the cancer:
• Production of cytokines
• Abnormalities of iron utilization
• Blunted erythropoietic response by inhibitory
cytokines
CAUSES.
• Most common etiology is chemotherapy or radiotherapy
• Patients at highest risk for therapy induced anemia are those that:
• Were anemic before therapy
• Undergo treatment with combined modalities (chemotherapy or radiotherapy)
MUST RULE OUT
• Immune hemolytic anemias
• Microangiopathic hemolysis
• Nutritional deficiences
TREATMENT GOALS
• Maintain hemoglobin (HGB) At a target range of 11to13g per dL During chemotherapy and/or
radiation therapy.
• Decrease the sequelae of anemia such as fatigue, shortness of breath , and requirements for
blood transfusions.
• Improve the patient’s quality of life.
CLINICAL PRESENTATION
• CLINICAL PRESENTATION AND DIAGNOSIS PATIENTS WITH CHEMOTHERAPY-INDUCED ANEMIA
MAY DIFFER IN CLINICAL PRESENTATION
Mild*
Moderate
Severe
HgB>10g/dL
HgB 8 to 10g/dL
<8 g/dL
May have fatigue or be
asymptomatic
Weakness, vertigo, concentration
impairment, dyspnea, headaches,
irritability
Weakness, vertigo,
concentration impairment,
dyspnea, headaches,
irritability
National Cancer Institute definition
SYMPTOMS THAT WARRANT TREATMENT
• Patients that have had blood transfusion in the past six months
• Past radiation therapy to greater than 20% of the skeleton
• Advanced age
• Cardiac disease
• Pulmonary disease
• Use of highly myelosuppressive therapy
TREATMENT
Immediate correction
with blood transfusion
Elderly, pt with severe
symptoms
Mildly symptomatic
initiate (rhu EPO)
TREATMENT
• rhuEPO mimics the actions of endogenous erythropoiten
• It is a glycoprotein produced and secreted by the kidney in response to low
oxygen tension
• On release into the blood-stream erythropoietin migrates to its site of action with
in the bone marrow, where it is responsible for the amplification and terminal
differentiation of erythroid progenitors and precursors for the formation of new
red blood cells
TREATMENT
• Two available commercially
• EPOETIN ALFA AND DARBEPOETIN ALFA
• Differ in half life therefore dosing schedules differ
TREATMENT
• Obtain baseline values for!
• Vit B12
• Folate
• Iron
• Hgb
• Reticulocytes
• Transferrin
• ferritin
Adequate stores
TREATMENT
Agent
Initial Dose and Schedule
Upward Dose adjustments
Darbepoetin
alfa
2.25 µg / kg SC weekly OR After 6 weeks, if < 1 g/dL increase in Hgb, increase
200µg SC every other week dose:
If was 2.25 µg / kg week
4.5µg / kg /wk
If was 200 µg / wk
300 µg / wk
Epoetin Alfa
150 units/kg SC three times
a week OR
40000 units SC weekly
After 4 week; if < 1 g/dL increase in Hgb, increase
dose:
If was 40000 units SC wk
60000
If was 150 units/kg SC three times a week
300 units /kg three times per week
If after an additional 4-6 weeks of therapy the patient fails to
respond, discontinue therapy unless there is clear evidence that
the patient is benefitting from therapy
TREATMENT
Agent
Initial Dose and Schedule
Darbepoetin
alfa
2.25 µg / kg SC weekly OR If transfusion independent Hgb
200µg SC every other week increases by >1g/ dL in any two
150 units/kg SC three times week period or if Hgb is greater
than 12g/dL, decrease the
a week OR
erythropoietin by 25%
40000 units SC weekly
If hgb is > than 13g/dL, hold dose
until Hgb falls below 12; then
reinitiate with 25% reduction
Epoetin Alfa
Downward dose adjustments
Source: National Oncology Alliance treatment Guidelines for Anemia; 2005
TREATMENT FAILURES
• NO FACTORS PREDICTIVE OF RESPONSIVENESS/UNRESPONSIVENESS
• ONE IS ENDOGENOUS ERYTHROPOIETIN LEVELS
• IF IT IS 1000 UNITS PER LITER OR GREATER SOME CLINICIANS WONT USE RHU EPO
• OTHERS USE 500 UNITS PER LITER AS THE CUT OFF POINT
MONITORING PARAMETERS
• Vit B12
• Folate
• Iron
• Hgb
• Reticulocytes
• Transferrin
• ferritin
Monitored every four weeks
once pt is begun on therapy
MONITORING PARAMETERS
• If Hgb rises too quickly; approx. 1g/dL during two weeks or exceeds 13g/dL; a dose reduction
is warranted
• During clinical studies patient that had increases in Hgb of 1g/dL during two weeks were
associated with an increased risk of neurologic events as seizures, cardiac events as cardiac
arrest,, CHF, HTN, vascular thrombosis/ischemia/infarction/AMI, fluid overload, edema
• If Hgb fails to increase after 4-6 weeks of therapy, a dose increase is warranted
THE ADMINISTRATION OF IRON
• TO IMPROVE RESPONSE IV ADMINISTRATION OF IRON CAN BE ATTEMPTED IF THE TRANSFERRIN
SATURATION IS 15% OR LESS, OR FERRITIN IS 100NG/ML OR LESS
SIDE EFFECTS
• SIDE EFFECTS ARE MINIMAL
• MEDULLARY BONE PAIN IS REPORTED MOST COMMONLY
• HYPERTENSION THAT DEVELOPS IN RENAL FAILURE PATIENTS BECAUSE OF THE INCREASED RED
BLOOD CELLS DOES NOT OCCUR USUALLY IN CANCER PATIENTS