RA’s Nasty Neutropenia:To stimulate or not to stimulate

Jennifer DayNHA ResidentMarch 26, 2010

Overview

ObjectivesPatient ProfileControversyPharmacy InterventionMonitoringOutcome

Objectives

Define neutropenia List five medications that may cause neutropenia State three patient populations where granulocyte-

colony 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: Neutropenia non-responsive to G-CSF PMH: Anemia, insomnia FH: Non-contributory SH: 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 doseIbuprofen 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)

AVSS: T=37 oC, HR=75, BP=135/75, RR= 17,SaO2=98% on RA

CNS No complaints

HEENT

RESP

Sore, inflamed mouth, pain with eating, white plaques; no cough/SOB

CVS No chest pain, iron=5 (), iron sat = 15% ()

GI

GU

Melena x 5/7, endoscopy normal; voiding per washroom, no burning/urgency/frequency (BUF)

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

(FSJ)

Oct 19

(PG)

Oct 27

Oct 28

Oct

29

WBC (x109) 0.7 <0.5 0.5 0.6

Hgb (g/L) 115 59 89 94

Plts (x106) 155 34 60 68

ANC (x109) -- 0.1 0.1 --

Transfused

Temp (oC) 38.9 37 37 36.5

Patient Profile – Medical Problems

Neutropenia Oral Mucositis Oral Thrush GI Bleed Anemia Pain Hypokalemia

Pharmacy Assessment – DRPs

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 ANC (10(1099/L)/L)

Risk Management

>1.5>1.5 None

1-1.51-1.5 No risk of significant infection; fever managed as outpt

0.5-10.5-1 Some risk of infection; fever can be managed as an outpt

<0.5<0.5 Significant risk of infection; fever should always be managed as inpt with IV ABX

<0.2<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?– Stable under heated conditions– Increase dopamine and endogenous opiate levels

Previously used for colon cancer, rheumatoid arthritis and as an antihelmithic– 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

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 agentSupportive 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

G-CSF

Neutropenia – Treatment Options

G-CSF– MOA:

G-CSF is produced by monocytes

Regulates neutrophil production, progenitor differentiation

Enhances phagocytic ability

Neutropenia – Treatment Options

G-CSF (Filgrastim)– Side-effects:

>10%: fever, rash, splenomegaly, bone pain, epistaxis

1-10%: hyper/hypotension, MI/arrhythmias, chest pain, headache, N/V, peritonitis

<1%: 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 feverprogressive infection or invasive fungal infectionspneumonia or sepsis syndromesevere (ANC less than 1) or anticipated prolonged

(greater than 10 days) neutropenia

PICO Question

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

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:

If fever or infection present empiric IV ABX and supportive care are recommended

“Treatment with G-CSF should be considered”

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: hospitalizeInfectious 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 stoppedMonitored for sign of infectionRecovered 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

Discontinue G-CSF in this pt– 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

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

KIDNEY SCr, urine output Weekly/Daily MD, Pharm

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

Epistaxis, peritonitis, dyspnea, wheezing

Daily MD, Nurse,

Pharm

CVS HR, BP, chest pain Daily Nurse, Pt

GI/GU Splenomegaly, N/V, hematuria

Daily Nurse, Pt, MD

KIDNEY

LIVER

Renal insufficiency

Alk Phos

Weekly MD, Pharm

HEME CBC (WBC >10) Daily MD, Pharm

DERM

MSK

Rash, bone pain, injection site rxn

Daily Nurse, Pt

Course in HospitalOct 27

Oct 28

Oct

29

Oct

30

Oct

31

Nov

1

Nov

2

Nov

3

Nov

4

Nov

5

Nov

6

WBC (x109)

<0.5 0.5 0.6 0.8 0.7 0.6 0.5 0.6 0.8 1.4 1.6

Hgb (g/L)

59 89 94 114 113 103 105 101 99 100 102

Plts (x106)

34 60 68 102 79 86 81 96 98 87 89

Neuts (x109)

0.1 0.1 -- 0.0 0.2 0.1 0.2 0.1 -- 0.5 0.6

G-CSF

Temp (oC)

37 36.5 37 37 36 36.5 36 36.5 38.5 38.5 37.3

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

Up to date Cps Toronto’s notes Micromedex Lexi drugs Asco guidelines Harm reduction article Reporting form article

Questions?