Transcript Therapy-Induced Encephalopathy

Therapy-Induced Encephalopathy
in an Allogeneic Hematopoietic
Stem Cell Transplant Patient
Beverly Mojica
Pharm.D. Candidate 2011
Western University of Health Sciences
Medicine Rotation
City of Hope
Outline
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Patient case
Background of encephalopathy
Causes of encephalopathy in HSCT recipients
Drug-induced encephalopathy
 Tacrolimus
 Methotrexate
 Cytarabine
 Rituximab
Future directions
Questions
Case: N.B.
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N.B. is a 62 year-old male (186.2 cm, 70.7 kg)
with a history of mantle cell lymphoma with CNS
involvement
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Admitted on 5/12/10 to City of Hope for an
allogeneic stem cell transplant from a matched
unrelated donor
Case: N.B.
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Past Medical History:
 History of prostate cancer
 Refractory mantle cell lymphoma with CNS
involvement (leptomeningeal)
 Bell’s Palsy
Family History:
 Father had prostate cancer
 Sister had an aneurysm and lives in Holland
Social History:
 Supported by his family including his wife
 Engineer who is self-employed as a consultant in
the Siemens/Diagnostic Imaging machines
 Smoked 1 pack of cigarettes for 20 years (quit in
1979)
 Drinks alcohol occasionally
Case: N.B.
Pertinent Medications:
Drug
Dose
Date
Rituximab
375 mg/m2
2002-2006
CVP + Rituximab x 8 cycles
2007
Cytarabine
4/24 to 4/27
Methotrexate
Tacrolimus
(1 mg/ml)
4000 mg q 12
hours IV x 6
doses
12 mg IT x 6
doses
1.1 mg IV daily
5/03 to 5/20
5/18 to 5/31
Case: N.B.
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Clinical History
 5/27:
 Confused overnight
 Tmax: 37 C
 5/28:
 Hallucinations in the morning
 Tmax: 37.2 C
 5/29:
 Confused overnight
 Blank staring
 Keppra 500 mg BID
 Tmax: 37.1 C
Case: N.B.
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Microbiology
 6/4:
 Stool: rapid CMV and HSV shell vial
cultures negative
 6/5:
 Aspergillus Ag negative by EIA
 Cryptococcal Ag serum negative
 Fungitell 1,3 Beta D glucan negative (65
pg/mL)
 Toxoplasma gondii from serum not
detected
Case: N.B.
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Electroencephalogram (EEG)
 Slow background (6 Hz) consistent with
encephalopathy
MRI Head
 6/9: No mass effect or focal abnormality
Cytology (spinal tap from omaya catheter)
 5/20 : No lymphoma in CSF
 6/15 : No lymphoma in CSF
Encephalopathy1
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Any diffuse disease of the brain that alters brain
function or structure
Causes:
 Infection (bacteria, virus, or prion)
 Metabolic or mitochondrial dysfunction
 Brain tumor or increased intracranial pressure
 Exposure to toxins (i.e. solvents, drugs,
alcohol, paints, industrial chemicals, and
certain metals)
 Radiation
 Trauma
 Poor nutrition
 Ischemia
Encephalopathy: Signs and
Symptoms1
Altered mental status
Progressive memory loss
Cognitive dysfunction
Personality changes
Difficulty concentrating
Lethargy
Myoclonus
Nystagmus
Tremor
Dysphagia
Dysarthria
Seizures
Coma
Death
Causes of Encephalopathy in
Allogeneic HSCT Recipients2
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Infection
 Fungi (Aspergillus, Candida), Gram-positive
bacteria
Toxoplasma organisms, Viral (CMV, human
herpes virus 6 or 7, Epstein-Barr, varicellazoster)
Vascular Disorders
 Thrombocytopenia, thrombosis, embolism
Tumor
Lymphoproliferative Disorders
Therapy-related encephalopathy
Tacrolimus3,4
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MOA: potent inhibition on T-lymphocyte
activation by inhibiting calcineurin phosphatase
activity
Tacrolimus3,6
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Absorption: Oral: Incomplete and variable
Distribution: 0.55-2.47 L/kg
Metabolism: Extensively hepatic via CYP3A4 to
eight possible metabolites
Excretion:
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Feces (~93%)
Urine (<2% as unchanged drug)
Biological half-life varies: 3.5-40.5 hours3
Tacrolimus Neurotoxicity
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Incidence: ~5-30%7
Posterior reversible encephalopathy syndrome
(PRES)
Initial manifestation:
 Sudden altered mental status, confusion,
headache, diminished spontaneity and
speech, lethargy, unconsciousness,
convulsions
Not dose-dependent2,6,7,8
Can occur at anytime after HSCT (usually within
1 month)
Tacrolimus Neurotoxicity2,5,6
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Mechanism unclear:
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Direct endothelial damage  injury to the
capillary bed  alteration of blood-brain
barrier (BBB)  white matter edema 
release of vasoactive peptides (endothelin,
thromboxane, prostacyclin)  vasospasm or
interruption of cerebral autoregulation
Tacrolimus Neurotoxicity5,7
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Radiologic Findings
 MRI: edema involving white matter in the
posterior portions of the cerebral hemispheres
(esp. bilaterally in the parieto-occipital
regions); hyperintense lesions (T2 weighted)
 CT: low attenuation of white matter
EEG: diffuse slowing or sharp epileptic
discharges
Methotrexate9,10
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MOA: inhibits DNA synthesis by irreversibly
binding to dihydrofolate reductase
Methotrexate10,11
Absorption: completely absorbed with parenteral
route
 Distribution: widely distributed throughout body
 Metabolism: <10% with hepatic aldehyde
and intestinal bacteriaoxidase
 Excretion: renal (~90% unchanged in the urine);
small amount in feces
 Renal impairment: CNS half-life may reach
19-44 hours
 Half-life: 4.5 -14 hours
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Methotrexate
Neurotoxicity12,13,14
Acute
 Onset: during or within hours after MTX
 Somnolence, confusion, fatigue, seizures
 Usually reversible
Subacute (3-15%)
 Onset: days to weeks post MTX treatment
 Stroke-like syndrome
 Hemiparesis, seizures, speech disorder
 Usually reversible
Chronic
 Onset: months to years
 Leukoencephalopathy
 Dementia, focal seizures, quadriparesis, stupor
 May or may not be reversible
Methotrexate Neurotoxicity15,16
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Incidence2
 < 10% with high dose IV MTX2
 Up to 40% with IT2
Risk factors:
 Dose-related
 Age >10
 Cranial irradiation
 Concomitant use of cytarabine, daunorubicin,
salicylates, sulfonamides or vinca alkaloids
Methotrexate Neurotoxicity12,14,15,17,18
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Mechanism not well established
 Direct toxic effects on neurons
 MTX inhibits dihydrofolate reductase
 Increased levels of adenosine
 Dilation of cerebral blood vessels
 Decreased synthesis of biogenic amine
neurotransmitters
 Elevated homocysteine:
 Endothelial cell injury
 Cerebrovascular infarcts
Methotrexate Neurotoxicity
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Route (IV, IT) and dose-dependent (cumulative
exposure)
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IT: 12-15 mg (> 100 mg)19
 Higher risk when IT MTX >50 mg in
combination with cranial irradiation or
systemic (IV) MTX 15
Recurrence rate: 10-56% upon rechallenge18
IT MTX must be preservative-free18
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IV > 1 g/m2 (or frequent IV)12,16,18
Methotrexate
Neurotoxicity14,15
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Management
 Antidote for reversal of MTX neurotoxicity:
aminophylline 2-5 mg/kg every 6 hours14,15,18
 Displaces adenosine from the receptor
 IT MTX overdose: glucarpidase 50 units/kg
bolus IV injection over 5 minutes 10
 Rapidly decrease MTX levels by up to 98%
in 30 minutes
 Not available commercially
 Call: 1-866-918-1731 for overnight shipping
Methotrexate Neurotoxicity10,16
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Prevention
 Folinic acid (leucovorin rescue)
 100 mg/m2 48 hours after MTX administration
q 3 hours x8 doses followed by 200 mg/m2
q 6 hours x4 doses16
 High dose did not compromise cure16
 Hydration10
 2.5 -3.5 L/m2 per day starting 12 hours prior to
MTX infusion
 Urinary alkalinazation10
 50 mL of D5W containing sodium bicarbonate
1 mEq/kg IV over 30 minutes q 4-6 hours
Cytarabine20
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MOA: primary action is inhibition of DNA
polymerase resulting in decreased DNA
synthesis and repair.
 Cytarabine is specific
for the S phase of the
cell cycle (blocks progression
from the G1 to the S phase).
Cytarabine20,21,22
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Absorption: Complete with IV
Distribution: Widely and rapidly in most tissues
 Crosses BBB with CSF levels of 40% to 50% of
plasma level
Metabolism: Primarily hepatic; 86% to 96% of dose
is metabolized to inactive metabolite
 IT little conversion to inactive metabolite
Excretion: Renal (~80%; 90% as inactive
metabolite) within 24 hours
Half-life
 IV: < 20 minutes21
 IT: 2-6 hours 20,21
Cytarabine Neurotoxicity13,21,23
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Route: Intrathecal, IV, liposomal23,13
 Cerebellar dysfunction (most common),
generalized encephalopathy, peripheral
neuropathy, and arachnoiditis, fecal and urinary
incontinence
 Cytotoxic levels of cytarabine may be maintained
for up to 24 hours after IT administration
 IT liposomal (sustained release) may maintain
cytotoxic concentrations of the drug in the CSF for
up to 14 days
 CSF exposure up to 40x that of standard Ara-C
Onset: As early as 2-5 days after treatment13
May resolve spontaneously within a few days or may
be permanent23,13
Cytarabine Neurotoxicity13,23
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Incidence: varies from 5-50%13,24
Risk factors13,23
 IV doses > 1 g/m2 23
 Total IV dose > 30 g (> 3g/ m2 every 12
hours)3
 IT dose (> 100 mg per week)21
 Age > 40 years of age13
 Prior cytarabine therapy
 Renal dysfunction
 IT, IT liposomal administration13
 Concomitant use with high-dose
chemotherapy (i.e. methotrexate)13,24
Cytarabine Neurotoxicity25,26
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MOA of how it causes encephalopathy:
-Cytotoxic effect25
-Immune-mediated mechanism is hypothesized26
Management:
 Cytarabine should be discontinued immediately13
 No standard treatment is available
 Corticosteroids (methylprednisolone,
dexamethasone)25,26
Prevention
 Concurrent use of corticosteroid with IT liposomal
cytarabine reduces risk of arachnoiditis21,24,25
Rituximab27
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MOA: B cell lysis by binding of the Fab domain
of rituximab to the CD20 antigen on B
lymphocytes and by recruitment of immune
effector functions by the Fc domain
 Complement-dependent
cytotoxicity (CDC)
 Antibody-dependent cellular
cytotoxicity (ADCC)
Rituximab27,28,29
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Absorption: I.V.: Immediate and results in a rapid
and sustained depletion of circulating and
tissue-based B cells
Metabolism: Hepatic
Distribution: Lymph nodes
Excretion: Uncertain; may undergo phagocytosis
and catabolism in the reticuloendothelial system
(RES)
 Median terminal half-life for NHL: 22 days
(range: 6-52 days)
Rituximab Neurotoxicity30
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Progressive Multifocal Leukoencephalopathy
(PML)
Incidence: Rare
 2 PML cases per 8000 rituximab treated SLE
patients
 Need to conduct more epidemiological studies
Risk factors:
 Need more studies
 Possibly low CD4 counts and low IgG levels
Rituximab Neurotoxicity27,30
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Clinical presentation
 Confusion/disorientation
 Motor weakness/hemiparesis
 Altered vision/speech
 Poor motor coordination
 Symptoms progress over weeks to months
MOA of how it causes encephalopathy1,2
 Unclear, but rituximab can decrease the
immune system and cause reactivation of the
Jakob-Creuzfeld (JC) virus
Rituximab Neurotoxicity30
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A retrospective analysis of patients diagnosed with
PML after rituximab treatment
 Cases from cancer centers or academic hospitals
(22), FDA reports (11), manufacturers database
(30), publications (18)
 Inclusion: rituximab therapy prior to PML, PML
confirmation with brain histology or MRI, no HIV
infection
 Patient Population (n=57)
 B-cell lymphoproliferative disorder (52)
 Systemic Lupus Erythmetous (2)
 Autoimmune pancytopenia (2)
 Immune thrombocytopenia purpura (1)
Rituximab Neurotoxicity30
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Onset:
 Median of 16 months (following rituximab
initiation)
 5.5 months (following last rituximab dose)
 6 rituximab doses preceded PML diagnosis
In the absence of immune reconstitution, case
fatality rate was 90%
 Survival rates up to 38% after hematopoietic
stem cell transplantation
Rituximab Neurotoxicity27,30
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Promptly evaluate any patient presenting with
neurological changes
 Consider neurology consultation, brain MRI
and lumbar puncture for suspected PM L
 Discontinue rituximab in patients who
develop PML
 Consider reduction/discontinuation of
concurrent chemotherapy or
immunosuppressants
 Risks versus benefits
Back to N.B.
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Clinical History
 6/16: confusion is clinically improving
 6/17: mental status seems to be slowly
improving
 6/20: confusion clinically stable
Acute altered mental status attributed to
tacrolimus CNS toxicity
Future Directions
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Need of biological markers or markers for
quantification of medication-induced
neurotoxicity
 Adenosine
 Choline (higher levels correlated with
demyelination)
Patterns
 MRI, CT, EEG
References
1. Author unknown. NINDS Encephalopathy Information Page. National Institute of
Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/encephalopathy/
encephalopathy.htm Last updated: 0212/2007. Date accessed: 06/17/2010
2. Nishiguchi T, Mochizuki K, Shakudo M, et al. CNS complications of Hematopoietic Stem
Cell Transplantation. AJR 2009; 192: 1002-1011
3. Prograf® (tacrolimus) injection package insert. Astellas Pharma.Deerfield, IL. Last
Revised: August 2009
5. Hinchey J, Chaves C, Appignani B, et al. A Reversible Posterior Leukoencephalopathy
Syndrome. NJEM (1996) 334:494-500.
6.Oliverio P, Restrepo L, Mitchell S, et al. Reversible Tacrolimus-induced Neurotoxicity
Isolated to the Brain Stem. Am J Neuroradiol (2000) 21: 1252-1254
7. Grimbert P., Azema C., Pastural M., et al. Tacrolimus (FK506)-induced severe and late
encephalopathy in a renal transplant recipient. Nephrol Dial Transplant (1999) 14: 24892491.
8. Chegounchi M, Hanna M, Neild G. Progressive neurological disease induced by
tacrolimus in a renal transplant recipient: Case presentation. BMC Nephrology 2006 Vol
7:1-3
9. Methotrexate for injection, USP package insert. Bedford Laboratories. Bedford, OH. Last
Revised: April 2005.
References
10. LaCasce A. Therapeutic use of high-dose methotrexate. UpToDate.
http://uptodate.com.proxy. westernu.edu/online/content/ topic.do?topicKey=chemge.
Last updated: 02/23/2009 Date Accessed: 06/16/2010
11. Lexi-Comp online, Lexi-Drugs Online. Hudson, Ohio Lexi-Comp, Inc. Methotrexate.
Last updated 6/18/10. Accessed 6/18/10.
12. Vazmar S, Schusseler P, Becker A, et al. Methotrexate-Associated Alterations of the
Folate and Methyl-transfer Pathway in the CSF of ALL Patients with and without
Symptoms of Neurotoxicity. Pediatr Blood Cancer (2009) 52:26-32
13. Wen P, Plotkin S. Neurologic complications on non-platinum cancer chemotherapy.
UpToDate. http://www.uptodate.com.proxy.westernu.edu /online/contecnt/topic.do?
topicKey=genl_onc Last updated: 12/27/2009. Date accessed: 06/17/2010.
14. Brugnoletti F, Morris EB, Laningham FH, et al. Recurrent Intrathecal Methotrexate
Induced Neurotoxicity in an Adolescent with Acute Lymphoblastic Leukemia: Serial
Clinical and Radiologic Findings. Pediatric Blood Cancer p.293-29515.
15. Shuper A, Stark B, Kornreich L, et al. Methotrexate-related Neurotoxicity in the
Treatment of Childhood Acute Lymphoblastic Leukemia. IMAJ (2002) Vol 4 p10501051
16. Hamidah A, Lope R, Latiff Z, et al. Prevention of Neurotoxicity by High-dose Folinic
Acid Rescue after High-dose methotrexate and Intrathecal methotrexate without
Compromising Cure inspite of Previous Transient Leukoencephalopathy after
Intrathecal Methotrexate. Annals Academy of Medicine. p743-744
References
17. Dicuonzo F, Salvati A, Palma M, et al. Posterior Reversible Encephalopathy
Syndrome Associate with Methotrexate Neurotoxicity: Conventional Magnetic
Resonance and Diffusion-Weighted Imaging Findings. J Child Neurol (2009)
24;8:1013-1018
18. Inaba H, Khan RB, Laningham FH, et al. Clinical and Radiological Characteristics of
Methotrexate-induced Acute Encephalopathy in Pediatric Patients with Cancer.
Annals of Oncology (2008) 19: 178-184
19. Finkelstein Y, Zevin S, Raikhlin-Eisenkraft B, Bentur Y. Intrathecal methotrexate
neurotoxicity: clinical correlated and antidotal treatment. Environmental Toxicology
and Pharmacology (2005) 19:721-725
20. Cytarabine for injection, USP package insert. Bedford Laboratories. Bedford, OH.
Last Revised: September 2008
21. Kwong YL, Yeung D, Chan J. Intrathecal Chemotherapy for Hematologic
Malignancies: Drugs and Toxicities. Ann Hematol (2009) 88: 193-201
22. Lexi-Comp online, Lexi-Drugs Online. Hudson, Ohio Lexi-Comp, Inc. Cytarabine. Last
updated 4/7/2010. Accessed 6/17/10.
23. Nielsen E, Brant J. Chemotherapy-Induced Neurotoxicity. AJN Supplement (2002)
16-19
References
24. Jabbour E, O’Brien S, Kantarjian H, et al. Neurologic complications associated with
intrathecal cytarabine given prophylatically in combination with high-dose
methotrexate and cytarabine with acute lymphocytic leukemia. Blood (2007) Vol 109,
No 8, pp 3214-3218
25. Hilgendorf I, Wolff D, Junghass C, et al. Neurological complications after Intrathecal
liposomal cytarabine application in patients after allogeneic hematopoietic stem cell
transplantation. Ann Hematol (2008) 87:1009-1012
26. Malhotra P, Mahi S, Lal V, et al. Cytarabine-Induced Neurotoxicity Responding to
Methylprednisolone. American Journal of Hematology 77: 416
27. Rituxan® (rituximab) for injection package insert. Genentech, Inc. South San
Francisco, CA. Las Revised: 02/2010
28. Lexi-Comp online, Lexi-Drugs Online. Hudson, Ohio Lexi-Comp, Inc. Rituximab. Last
updated 6/18/10. Accessed 6/18/10.
29. Cartron G, Blasco H, Paintaud G, Watier H, Le Guellec C. Pharmacokinetics of
rituximab and its clinical use: thought for the best use? Crit Rev Oncol Hematol
62(1):43-52 (2007 Apr).
30. Carson K, Evens AM, Richey EA. Progressive multifocal leukoencephalopathy after
rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on
Adverse Drug Events and Reports project. BLOOD 05/14/2009. Vol 113, No 20.
pp4833-4840.
Questions