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Therapy-Induced Encephalopathy in an Allogeneic Hematopoietic Stem Cell Transplant Patient

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Therapy-Induced Encephalopathy in an Allogeneic Hematopoietic Stem Cell Transplant Patient Beverly Mojica Pharm.D. Candidate 2011 Western University of Health Sciences – PowerPoint PPT presentation

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Title: Therapy-Induced Encephalopathy in an Allogeneic Hematopoietic Stem Cell Transplant Patient


1
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
2
Outline
  • Patient case
  • Background of encephalopathy
  • Causes of encephalopathy in HSCT recipients
  • Drug-induced encephalopathy
  • Tacrolimus
  • Methotrexate
  • Cytarabine
  • Rituximab
  • Future directions
  • Questions

3
Case N.B.
  • N.B. is a 62 year-old male (186.2 cm, 70.7 kg)
    with a history of mantle cell lymphoma with CNS
    involvement
  • Admitted on 5/12/10 to City of Hope for an
    allogeneic stem cell transplant from a matched
    unrelated donor

4
Case N.B.
  • Past Medical History
  • History of prostate cancer
  • Refractory mantle cell lymphoma with CNS
    involvement (leptomeningeal)
  • Bells 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

5
Case N.B.
  • Pertinent Medications

6
Case N.B.
  • 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

7
Case N.B.
  • 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

8
Case N.B.
  • 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

9
Encephalopathy1
  • 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

10
Encephalopathy Signs and Symptoms1
11
Causes of Encephalopathy in Allogeneic HSCT
Recipients2
  • Infection
  • Fungi (Aspergillus, Candida), Gram-positive
    bacteria
  • Toxoplasma organisms, Viral (CMV, human herpes
    virus 6 or 7, Epstein-Barr, varicella-zoster)
  • Vascular Disorders
  • Thrombocytopenia, thrombosis, embolism
  • Tumor
  • Lymphoproliferative Disorders
  • Therapy-related encephalopathy

12
Tacrolimus3,4
  • MOA potent inhibition on T-lymphocyte activation
    by inhibiting calcineurin phosphatase activity

13
Tacrolimus3,6
  • Absorption Oral Incomplete and variable
  • Distribution 0.55-2.47 L/kg
  • Metabolism Extensively hepatic via CYP3A4 to
    eight possible metabolites
  • Excretion
  • Feces (93)
  • Urine (lt2 as unchanged drug)
  • Biological half-life varies 3.5-40.5 hours3

14
Tacrolimus Neurotoxicity
  • Incidence 5-307
  • 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)

15
Tacrolimus Neurotoxicity2,5,6
  • Mechanism unclear
  • 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

16
Tacrolimus Neurotoxicity5,7
  • 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

17
Methotrexate9,10
  • MOA inhibits DNA synthesis by irreversibly
    binding to dihydrofolate reductase

18
Methotrexate10,11
  • Absorption completely absorbed with parenteral
    route
  • Distribution widely distributed throughout body
  • Metabolism lt10 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

19
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

20
Methotrexate Neurotoxicity15,16
  • Incidence2
  • lt 10 with high dose IV MTX2
  • Up to 40 with IT2
  • Risk factors
  • Dose-related
  • Age gt10
  • Cranial irradiation
  • Concomitant use of cytarabine, daunorubicin,
    salicylates, sulfonamides or vinca alkaloids

21
Methotrexate Neurotoxicity12,14,15,17,18
  • 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

22
Methotrexate Neurotoxicity
  • Route (IV, IT) and dose-dependent (cumulative
    exposure)
  • IV gt 1 g/m2 (or frequent IV)12,16,18
  • IT 12-15 mg (gt 100 mg)19
  • Higher risk when IT MTX gt50 mg in combination
    with cranial irradiation or systemic (IV) MTX
    15
  • Recurrence rate 10-56 upon rechallenge18
  • IT MTX must be preservative-free18

23
Methotrexate Neurotoxicity14,15
  • 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

24
Methotrexate Neurotoxicity10,16
  • 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

25
Cytarabine20
  • 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).

26
Cytarabine20,21,22
  • 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 lt 20 minutes21
  • IT 2-6 hours 20,21

27
Cytarabine Neurotoxicity13,21,23
  • 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

28
Cytarabine Neurotoxicity13,23
  • Incidence varies from 5-5013,24
  • Risk factors13,23
  • IV doses gt 1 g/m2 23
  • Total IV dose gt 30 g (gt 3g/ m2 every 12 hours)3
  • IT dose (gt 100 mg per week)21
  • Age gt 40 years of age13
  • Prior cytarabine therapy
  • Renal dysfunction
  • IT, IT liposomal administration13
  • Concomitant use with high-dose chemotherapy (i.e.
    methotrexate)13,24

29
Cytarabine Neurotoxicity25,26
  • 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

30
Rituximab27
  • 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)

31
Rituximab27,28,29
  • 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)

32
Rituximab Neurotoxicity30
  • 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

33
Rituximab Neurotoxicity27,30
  • 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

34
Rituximab Neurotoxicity30
  • 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 (n57)
  • B-cell lymphoproliferative disorder (52)
  • Systemic Lupus Erythmetous (2)
  • Autoimmune pancytopenia (2)
  • Immune thrombocytopenia purpura (1)

35
Rituximab Neurotoxicity30
  • 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

36
Rituximab Neurotoxicity27,30
  • 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

37
Back to N.B.
  • 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

38
Future Directions
  • Need of biological markers or markers for
    quantification of medication-induced
    neurotoxicity
  • Adenosine
  • Choline (higher levels correlated with
    demyelination)
  • Patterns
  • MRI, CT, EEG

39
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
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    Reversible Posterior Leukoencephalopathy
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    Reversible Tacrolimus-induced Neurotoxicity
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    Tacrolimus (FK506)-induced severe and late
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References
  • 10. LaCasce A. Therapeutic use of high-dose
    methotrexate. UpToDate. http//uptodate.com.proxy
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41
References
  • 17. Dicuonzo F, Salvati A, Palma M, et al.
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    after allogeneic hematopoietic stem cell
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43
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