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RA’s Nasty Neutropenia:
To stimulate or not to stimulate
Jennifer Day
NHA Resident
March 26, 2010
Overview
Objectives
 Patient Profile
 Controversy
 Pharmacy Intervention
 Monitoring
 Outcome

Objectives




Define neutropenia
List five medications that may cause neutropenia
State three patient populations where granulocytecolony stimulating factor (G-CSF) therapy would be
appropriate
Reiterate the recommendations presented by the
British Columbia Centre for Disease Control
(BCCDC) for cocaine-induced neutropenia
Patient Profile – Presentation



ID:
49 yo 1st Nations female
CC: Sore, inflamed mouth, hurt to eat
HPI: • 1 yr hx of neutropenia, recurrent mucositis
? 2o to laced crack-cocaine
• G-CSF therapy started
• Presented to Ft. St. James (FSJ) hospital
after 1st dose w/ fever, chest pain
• Transferred to UHNBC-PG
Patient Profile – Presentation





DX:
PMH:
FH:
SH:
Neutropenia non-responsive to G-CSF
Anemia, insomnia
Non-contributory
Hx of EtOH abuse, gas-huffing,
crack-cocaine use x ~15 years
 Smoking, casual use, last use 3 weeks
Allergies: codeine = itching
Patient Profile – Medications

MPTA:
G-CSF 300mcg SQ daily x 1 dose
Ibuprofen 400mg PO tid
Vitamin B6 50mg PO daily
Vitamin B12 100mg PO daily
Calcium/Vit D 500mg/125 IU PO bid
Ferrous sulphate 300mg PO bid
Oxazepam 15mg PO hs prn
Patient Profile – Medications

UHNBC:
Ceftazidime 2g IV q8h
Gentamicin 360mg IV q24h
Lansoprazole 30mg PO bid
Replavite 1 tab PO daily
Folate 5mg PO daily
Ferrous sulphate 600mg PO bid
Vitamin C 1000mg PO daily
Vitamin B12 1000mcg IM qmonthly
Patient Profile – Medications

UHNBC: Nystatin 500,000 units PO tid, swish and
swallow
KCl SR 24mEq PO q4h x 3 doses then 
KCl SR 8mEq PO bid
Benzydamine 5mL PO qid, swish and spit
Magic Mouthwash 10mL PO prn
Hydromorphone 2mg PO q4h prn
Dimenhydrinate 25-50mg PO q4-6h prn
Patient Profile – Review of Systems
VITALS
(Oct 27)
CNS
AVSS: T=37 oC, HR=75, BP=135/75, RR= 17,
SaO2=98% on RA
HEENT
RESP
CVS
Sore, inflamed mouth, pain with eating, white
plaques; no cough/SOB
GI
GU
Melena x 5/7, endoscopy normal; voiding per
washroom, no burning/urgency/frequency (BUF)
No complaints
No chest pain, iron=5 (), iron sat = 15% ()
Patient Profile – Review of Systems
LIVER
KIDNEY
SCr=46 (stable), CrCl=151; splenomegaly;
LFT WNL
ENDOCRINE
BG=5.3 (random)
MSK/EXTR/SKIN
Slight facial edema, body aches
FLUID STATUS
No complaints; K=2.8 (), Na=134 ()
Patient Profile – Neutropenia
WBC (x10 )
Hgb (g/L)
9
Plts (x106)
ANC (x109)
(FSJ)
Oct
19
(PG)
Oct
27
Oct
28
Oct
29
0.7
<0.5
0.5
0.6
115
59
89
94
155
34
60
68
--
0.1
0.1
--
37
36.5
Transfused
Temp (oC)
38.9
37
Patient Profile – Medical Problems
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Neutropenia
Oral Mucositis
Oral Thrush
GI Bleed
Anemia
Pain
Hypokalemia
Pharmacy Assessment – DRPs
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AR is experiencing neutropenia
AR is experiencing side-effects of G-CSF
AR is experiencing oral mucositis pain
AR is experiencing oral thrush
AR is experiencing a GI bleed
AR is experiencing hypokalemia
AR is experiencing anemia
AR is experiencing pain
Haematopoiesis – Overview


The formation of blood components from
haematopoiesis stem cells found in bone marrow
All blood cells are of three lineages
– Erythroid cells: red blood cells
– Lymphoid cells: adaptive immune system
– Myeloid cells: granulocytes, macrophages
Neutropenia – Overview



Definition: ANC less than 1.5x109/L
– ANC = WBC x percent (PMNs + bands) ÷ 100
Drug-induced:
– Decreased production or peripheral destruction
 Alkylating agents, antimetabolites,
anticonvulsants, antipsychotics, antibiotics,
anti-inflammatory agents, anti-thyroid
medications, antibiotics, levamisole
Risks: mucositis, infection, sepsis
Neutropenia – Overview
ANC
Risk Management
(109/L)
None
>1.5
1-1.5
No risk of significant infection; fever managed as outpt
0.5-1
Some risk of infection; fever can be managed as an outpt
<0.5
Significant risk of infection; fever should always be
managed as inpt with IV ABX
<0.2
Very significant risk of infection; fever should always be
managed on an inpt basis with IV ABX
Levamisole – Overview

Why lace cocaine with levamisole?
–
–

Previously used for colon cancer, rheumatoid
arthritis and as an antihelmithic
–

Stable under heated conditions
Increase dopamine and endogenous opiate levels
Imidazothiazole derivative ABX
Hasn’t been available commercially since 2005
–
–
Caused neutropenia by ?immune-mediated destruction
Still available in USA for veterinary use
Pharmacy Assessment – Goals

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
Stop disease process
Manage patient’s symptoms
Prevent disease
Normalize physiological parameters
Minimize side-effects of therapy
Neutropenia – Treatment Options

Alternatives for drug-induced neutropenia:
– 1st line:
 Discontinue
offending agent
 Supportive care (ABX if febrile, indicated)
–
2nd line:
 Colony-Stimulating
Factor hormone
– G-CSF (Filgrastim)
– Pegylated G-CSF (Pegfilgrastim)
– GM-CSF (Sargramostim)
– 3rd line:
 If no response to above
– IV immunoglobulin
– Granulocyte infusion
Neutropenia – Treatment Options

G-CSF
– MOA:
 G-CSF
is produced
by monocytes
 Regulates
neutrophil
production,
progenitor
differentiation
 Enhances
phagocytic ability
G-CSF
Neutropenia – Treatment Options

G-CSF (Filgrastim)
– Side-effects:
 >10%: fever, rash, splenomegaly, bone pain, epistaxis
 1-10%:
 <1%:
hyper/hypotension, MI/arrhythmias, chest pain,
headache, N/V, peritonitis
pulmonary infiltrates, tachycardia, hematuria,
wheezing, renal insufficiency, injection site
reaction, ARDS, allergic reactions, arthralgias,
dyspnea, facial edema, hemoptysis
Controversy


G-CSF indications for patients with:
– Febrile neutropenia due to chemotherapy
– Specific chemotherapy protocols
– Bone marrow transplants
– Human Immunodeficiency Virus (HIV)
– Chronic non-drug induced neutropenia
G-CSF use in non-febrile, otherwise healthy
patients is not well established
Controversy

G-CSF use for the treatment of neutropenia
– Should not be used routinely in afebrile pts
– Little supporting evidence as an adjunct to ABX
therapy in febrile pts
– May be considered in high risk neutropenic
febrile pts or serious infectious complications:
 advanced
age (older than 65 years)
 fever at hospitalization or unstable fever
 progressive infection or invasive fungal infections
 pneumonia or sepsis syndrome
 severe (ANC less than 1) or anticipated prolonged
(greater than 10 days) neutropenia
PICO Question
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P: In a 49 year old First Nations woman who
chronically smokes crack-cocaine and is currently
experiencing afebrile neutropenia secondary to
levamisole-laced cocaine
I: is G-CSF therapy versus
C: no G-CSF therapy
O: effective in decreasing mortality?
Search Strategy
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
Databases:
– PubMed, Embase, Google Scholar
Search terms:
– Cocaine-induced
– Levamisole
– Neutropenia
– G-CSF
Results: anger and frustration
Literature Review – Evidence

Levamisole tainted cocaine causing severe
neutropenia in Alberta and British Columbia,
Harm Reduction Journal; 2009
– Retrospective, 42 cases
– 93% used crack-cocaine; 72% smoked
– Conclusions:
fever or infection present  empiric IV ABX and
supportive care are recommended
 “Treatment with G-CSF should be considered”
 If
Literature Review – Evidence

Agranulocytosis associated with levamisole in
cocaine, BCCDC update: April 2009
– Developed standard case report form
– Diagnostic tests: CBC & diff, urine for drugs
– Management:
 If
ANC <1.0, febrile with active infection: hospitalize
 Infectious work-up, broad spectrum ABX
 “G-CSF should not be started until consultation
with haematologist”
–
Recovery in 7-10 days
Literature Review – Evidence

Neutropenia during treatment of rheumatoid
arthritis (RA) with levamisole, Annals of
Rheumatic Diseases, 1978
– 60 pts with RA treated with levamisole
– 35% showed persistent decrease of neutrophils
– 10% developed severe neutropenia (ANC <1.0)
– Management:
 Therapy
stopped
 Monitored for sign of infection
 Recovered within 10 days
Bottom Line

Should we use G-CSF in this pt population?
– May be considered in high risk neutropenic
febrile pts or those at risk of serious infectious
complications
– No evidence for decreased mortality or
increased benefit over appropriate ABX for
febrile neutropenia
– Consider cost vs. benefits
– BCCDC advises against routine use
– More studies and clear guidelines needed
Weighing the Options

Pros
– Not contraindicated
– Possibility of effect

Cons
– No evidence
– Not clearly indicated
– Hasn’t worked in past
– Experiencing side-effects
– Expensive
– ? Mortality benefits
Pharmacy Recommendations
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Discontinue G-CSF in this pt
–
–
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Experiencing side-effects
No evidence, no effect
Report case to BCCDC, counsel pt on risks
Continue to monitor temperature, signs of systemic
infection
Increase nystatin 500,000 units PO qid, swish and
swallow
Change Magic Mouthwash 5mL PO qid ac meals
Increase benzydamine 15mL PO qid, swish and spit
Outcome
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G-CSF 300 mcg SQ daily Oct 29-Nov 5
Bone marrow biopsy  active
Awaiting HIV serology tests
D/C ABX, lansoprazole
Pt able to eat regular meals with minimal pain and
discomfort
Oral thrush resolved
Monitoring Plan – Efficacy
Parameter
Frequency
Who?
CNS
Temp < 38 oC
Twice daily
Nurse, Pt
HEENT
RESP
Mucositis, cough, SOB,
RR, O2Sat
Daily
MD, Nurse,
Pharm
CVS
HR, BP
Daily
Nurse
GI/GU
Burning, urgency,
frequency
Daily
Nurse, Pt
Weekly/Daily
MD, Pharm
KIDNEY SCr, urine output
HEME
CBC (Neuts >1.5x109/L)
Daily
MD, Pharm
DERM
MSK
Chills, night sweats,
facial edema
Daily
Nurse, Pt
Monitoring Plan – Toxicity
Parameter
Frequency
Who?
CNS
Temp < 38 oC, headache Twice daily
Nurse, Pt
HEENT
RESP
CVS
Epistaxis, peritonitis,
dyspnea, wheezing
Daily
MD, Nurse,
Pharm
HR, BP, chest pain
Daily
Nurse, Pt
GI/GU
Splenomegaly, N/V,
hematuria
Daily
Nurse, Pt,
MD
Weekly
MD, Pharm
Daily
MD, Pharm
Daily
Nurse, Pt
KIDNEY Renal insufficiency
Alk Phos
LIVER
CBC (WBC >10)
HEME
DERM
MSK
Rash, bone pain,
injection site rxn
Course in Hospital
WBC
Oct
27
Oct
28
Oct
29
Oct
30
Oct
31
Nov
1
Nov
2
Nov
3
Nov
4
Nov
5
Nov
6
<0.5
0.5
0.6
0.8
0.7
0.6
0.5
0.6
0.8
1.4
1.6
59
89
94
114
113
103
105
101
99
100
102
34
60
68
102
79
86
81
96
98
87
89
0.1
0.1
--
0.0
0.2
0.1
0.2
0.1
--
0.5
0.6









37
37
36
36.5
36
36.5
38.5
38.5
37.3
(x109)
Hgb
(g/L)
Plts
(x106)
Neuts
(x109)
G-CSF
Temp
(oC)
37
36.5
Outcome

Saturday, Nov 7, 2009
– ANC = 1.2 x109/L
– G-CSF dose given (18 doses total)
– Pt stable, afebrile, no signs of further infection
– Transferred back to FSJ
– Lost to follow-up
Addendum
References
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Up to date
Cps
Toronto’s notes
Micromedex
Lexi drugs
Asco guidelines
Harm reduction article
Reporting form article
Questions?