therapy-induced encephalopathy in an allogeneic hematopoietic stem cell transplant patient beverly...

Therapy-Induced Encephalopathy Therapy-Induced Encephalopathy in an Allogeneic Hematopoietic in an Allogeneic Hematopoietic

Stem Cell Transplant PatientStem Cell Transplant Patient

Beverly MojicaBeverly Mojica

Pharm.D. Candidate 2011Pharm.D. Candidate 2011

Western University of Health SciencesWestern University of Health Sciences

Medicine RotationMedicine Rotation

City of HopeCity of Hope

OutlineOutline Patient casePatient case Background of encephalopathyBackground of encephalopathy Causes of encephalopathy in HSCT recipientsCauses of encephalopathy in HSCT recipients Drug-induced encephalopathyDrug-induced encephalopathy

TacrolimusTacrolimus MethotrexateMethotrexate CytarabineCytarabine RituximabRituximab

Future directionsFuture directions QuestionsQuestions

Case: N.B.Case: N.B.

N.B. is a 62 year-old male (186.2 cm, 70.7 kg) N.B. is a 62 year-old male (186.2 cm, 70.7 kg) with a history of mantle cell lymphoma with CNS with a history of mantle cell lymphoma with CNS involvement involvement

Admitted on 5/12/10 to City of Hope for an Admitted on 5/12/10 to City of Hope for an allogeneic stem cell transplant from a matched allogeneic stem cell transplant from a matched unrelated donorunrelated donor

Case: N.B.Case: N.B. Past Medical History:Past Medical History:

History of prostate cancer History of prostate cancer Refractory mantle cell lymphoma with CNS involvement Refractory mantle cell lymphoma with CNS involvement

(leptomeningeal)(leptomeningeal) Bell’s PalsyBell’s Palsy

Family History:Family History: Father had prostate cancerFather had prostate cancer Sister had an aneurysm and lives in HollandSister had an aneurysm and lives in Holland

Social History:Social History: Supported by his family including his wifeSupported by his family including his wife Engineer who is self-employed as a consultant in the Engineer who is self-employed as a consultant in the

Siemens/Diagnostic Imaging machinesSiemens/Diagnostic Imaging machines Smoked 1 pack of cigarettes for 20 years (quit in 1979)Smoked 1 pack of cigarettes for 20 years (quit in 1979) Drinks alcohol occasionallyDrinks alcohol occasionally

Case: N.B.Case: N.B.Pertinent Medications:Pertinent Medications:

Drug Dose Date

Rituximab 375 mg/m2 2002-2006

CVP + Rituximab x 8 cycles 2007

Cytarabine 4000 mg q 12 hours IV x 6 doses

4/24 to 4/27

Methotrexate 12 mg IT x 6 doses

5/03 to 5/20

Tacrolimus (1 mg/ml)

1.1 mg IV daily 5/18 to 5/31

Case: N.B.Case: N.B. Clinical HistoryClinical History

5/27:5/27: Confused overnightConfused overnight Tmax: 37 CTmax: 37 C

5/28:5/28: Hallucinations in the morningHallucinations in the morning Tmax: 37.2 CTmax: 37.2 C

5/29: 5/29: Confused overnightConfused overnight Blank staring Blank staring

Keppra 500 mg BID Keppra 500 mg BID Tmax: 37.1 CTmax: 37.1 C

Case: N.B.Case: N.B. MicrobiologyMicrobiology

6/4: 6/4: Stool: rapid CMV and HSV shell vial cultures Stool: rapid CMV and HSV shell vial cultures

negativenegative 6/5:6/5:

Aspergillus Ag negative by EIAAspergillus Ag negative by EIA Cryptococcal Ag serum negativeCryptococcal Ag serum negative Fungitell 1,3 Beta D glucan negative (65 Fungitell 1,3 Beta D glucan negative (65

pg/mL)pg/mL) Toxoplasma gondii from serum not detectedToxoplasma gondii from serum not detected

Case: N.B.Case: N.B.

Electroencephalogram (EEG)Electroencephalogram (EEG) Slow background (6 Hz) consistent with Slow background (6 Hz) consistent with

encephalopathyencephalopathy MRI HeadMRI Head

6/9: No mass effect or focal abnormality6/9: No mass effect or focal abnormality Cytology (spinal tap from omaya catheter)Cytology (spinal tap from omaya catheter)

5/20 : No lymphoma in CSF 5/20 : No lymphoma in CSF 6/15 : No lymphoma in CSF6/15 : No lymphoma in CSF

EncephalopathyEncephalopathy11

Any diffuse disease of the brain that alters brain Any diffuse disease of the brain that alters brain function or structure function or structure

Causes:Causes: Infection (bacteria, virus, or prion)Infection (bacteria, virus, or prion) Metabolic or mitochondrial dysfunctionMetabolic or mitochondrial dysfunction Brain tumor or increased intracranial pressureBrain tumor or increased intracranial pressure Exposure to toxins (i.e. solvents, drugs, alcohol, Exposure to toxins (i.e. solvents, drugs, alcohol,

paints, industrial chemicals, and certain metals)paints, industrial chemicals, and certain metals) RadiationRadiation TraumaTrauma Poor nutritionPoor nutrition IschemiaIschemia

Encephalopathy: Signs and Encephalopathy: Signs and SymptomsSymptoms11

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 Causes of Encephalopathy in Allogeneic HSCT RecipientsAllogeneic HSCT Recipients22

InfectionInfection Fungi (Aspergillus, Candida), Gram-positive Fungi (Aspergillus, Candida), Gram-positive

bacteriabacteria

Toxoplasma organisms, Viral (CMV, human herpes Toxoplasma organisms, Viral (CMV, human herpes virus 6 or 7, Epstein-Barr, varicella-zoster)virus 6 or 7, Epstein-Barr, varicella-zoster)

Vascular DisordersVascular Disorders Thrombocytopenia, thrombosis, embolismThrombocytopenia, thrombosis, embolism

Tumor Tumor Lymphoproliferative DisordersLymphoproliferative Disorders Therapy-related encephalopathyTherapy-related encephalopathy

TacrolimusTacrolimus3,43,4

MOA: potent inhibition on T-lymphocyte MOA: potent inhibition on T-lymphocyte activation by inhibiting calcineurin phosphatase activation by inhibiting calcineurin phosphatase activity activity

TacrolimusTacrolimus3,63,6

Absorption: Oral: Incomplete and variableAbsorption: Oral: Incomplete and variable Distribution: 0.55-2.47 L/kgDistribution: 0.55-2.47 L/kg Metabolism: Extensively hepatic via CYP3A4 to Metabolism: Extensively hepatic via CYP3A4 to

eight possible metaboliteseight possible metabolites Excretion: Excretion:

Feces (~93%)Feces (~93%) Urine (<2% as unchanged drug)Urine (<2% as unchanged drug)

Biological half-life varies: 3.5-40.5 hoursBiological half-life varies: 3.5-40.5 hours33

Tacrolimus NeurotoxicityTacrolimus Neurotoxicity Incidence: ~5-30%Incidence: ~5-30%77

Posterior reversible encephalopathy syndrome Posterior reversible encephalopathy syndrome (PRES)(PRES)

Initial manifestation:Initial manifestation: Sudden altered mental status, confusion, Sudden altered mental status, confusion,

headache, diminished spontaneity and speech, headache, diminished spontaneity and speech, lethargy, unconsciousness, convulsionslethargy, unconsciousness, convulsions

Not dose-dependentNot dose-dependent2,6,7,82,6,7,8

Can occur at anytime after HSCT (usually within 1 Can occur at anytime after HSCT (usually within 1 month)month)

Tacrolimus NeurotoxicityTacrolimus Neurotoxicity2,5,62,5,6

Mechanism unclear:Mechanism unclear: Direct endothelial damage Direct endothelial damage injury to the injury to the

capillary bed capillary bed alteration of blood-brain alteration of blood-brain barrier (BBB) barrier (BBB) white matter edema white matter edema release of vasoactive peptides (endothelin, release of vasoactive peptides (endothelin, thromboxane, prostacyclin) thromboxane, prostacyclin) vasospasm or vasospasm or interruption of cerebral autoregulationinterruption of cerebral autoregulation

Tacrolimus NeurotoxicityTacrolimus Neurotoxicity5,75,7

Radiologic FindingsRadiologic Findings MRI: edema involving white matter in the MRI: edema involving white matter in the

posterior portions of the cerebral hemispheres posterior portions of the cerebral hemispheres (esp. bilaterally in the parieto-occipital (esp. bilaterally in the parieto-occipital regions); hyperintense lesions (T2 weighted)regions); hyperintense lesions (T2 weighted)

CT: low attenuation of white matterCT: low attenuation of white matter EEG: diffuse slowing or sharp epileptic EEG: diffuse slowing or sharp epileptic

dischargesdischarges

MethotrexateMethotrexate9,109,10

MOA: inhibits DNA synthesis by irreversibly MOA: inhibits DNA synthesis by irreversibly binding to dihydrofolate reductasebinding to dihydrofolate reductase

MethotrexateMethotrexate10,1110,11

Absorption: completely absorbed with parenteral Absorption: completely absorbed with parenteral routeroute

Distribution: widely distributed throughout bodyDistribution: widely distributed throughout body Metabolism: <10% with hepatic aldehydeMetabolism: <10% with hepatic aldehyde

and intestinal bacteriaoxidaseand intestinal bacteriaoxidase Excretion: renal (~90% unchanged in the urine); Excretion: renal (~90% unchanged in the urine);

small amount in fecessmall amount in feces Renal impairment: CNS half-life may reach 19-Renal impairment: CNS half-life may reach 19-

44 hours44 hours Half-life: 4.5 -14 hoursHalf-life: 4.5 -14 hours

Methotrexate Methotrexate NeurotoxicityNeurotoxicity12,13,1412,13,14

AcuteAcute Onset: during or within hours after MTXOnset: during or within hours after MTX Somnolence, confusion, fatigue, seizuresSomnolence, confusion, fatigue, seizures Usually reversibleUsually reversible

Subacute (3-15%)Subacute (3-15%) Onset: days to weeks post MTX treatmentOnset: days to weeks post MTX treatment Stroke-like syndromeStroke-like syndrome

Hemiparesis, seizures, speech disorderHemiparesis, seizures, speech disorder Usually reversibleUsually reversible

ChronicChronic Onset: months to yearsOnset: months to years LeukoencephalopathyLeukoencephalopathy

Dementia, focal seizures, quadriparesis, stuporDementia, focal seizures, quadriparesis, stupor May or may not be reversibleMay or may not be reversible

Methotrexate NeurotoxicityMethotrexate Neurotoxicity15,1615,16

IncidenceIncidence22

< 10% with high dose IV MTX< 10% with high dose IV MTX22

Up to 40% with ITUp to 40% with IT22

Risk factors:Risk factors: Dose-relatedDose-related Age >10Age >10 Cranial irradiationCranial irradiation Concomitant use of cytarabine, daunorubicin, Concomitant use of cytarabine, daunorubicin,

salicylates, sulfonamides or vinca alkaloids salicylates, sulfonamides or vinca alkaloids

Methotrexate NeurotoxicityMethotrexate Neurotoxicity12,14,15,17,1812,14,15,17,18

Mechanism not well establishedMechanism not well established Direct toxic effects on neuronsDirect toxic effects on neurons MTX inhibits dihydrofolate reductaseMTX inhibits dihydrofolate reductase

Increased levels of adenosineIncreased levels of adenosine Dilation of cerebral blood vesselsDilation of cerebral blood vessels Decreased synthesis of biogenic amine Decreased synthesis of biogenic amine

neurotransmittersneurotransmitters Elevated homocysteine:Elevated homocysteine:

Endothelial cell injuryEndothelial cell injury Cerebrovascular infarctsCerebrovascular infarcts

Methotrexate NeurotoxicityMethotrexate Neurotoxicity Route (IV, IT) and dose-dependent (cumulative Route (IV, IT) and dose-dependent (cumulative

exposure) exposure) IV IV >> 1 g/m2 (or frequent IV) 1 g/m2 (or frequent IV)12,16,1812,16,18

IT: 12-15 mg (> 100 mg)IT: 12-15 mg (> 100 mg)1919

Higher risk when IT MTX >50 mg in Higher risk when IT MTX >50 mg in combination with cranial irradiation or combination with cranial irradiation or

systemic (IV) MTX systemic (IV) MTX 1515

Recurrence rate: 10-56% upon rechallengeRecurrence rate: 10-56% upon rechallenge1818

IT MTX must be preservative-freeIT MTX must be preservative-free1818


ManagementManagement Antidote for reversal of MTX neurotoxicity: Antidote for reversal of MTX neurotoxicity:

aminophylline 2-5 mg/kg every 6 hoursaminophylline 2-5 mg/kg every 6 hours14,15,1814,15,18

Displaces adenosine from the receptorDisplaces adenosine from the receptor IT MTX overdose: glucarpidase 50 units/kg IT MTX overdose: glucarpidase 50 units/kg

bolus IV injection over 5 minutes bolus IV injection over 5 minutes 1010

Rapidly decrease MTX levels by up to 98% in Rapidly decrease MTX levels by up to 98% in 30 minutes30 minutes

Not available commerciallyNot available commercially Call: 1-866-918-1731 for overnight shippingCall: 1-866-918-1731 for overnight shipping


PreventionPrevention Folinic acid (leucovorin rescue)Folinic acid (leucovorin rescue)

100 mg/m2 48 hours after MTX administration q 3 hours 100 mg/m2 48 hours after MTX administration q 3 hours x8 doses followed by 200 mg/m2 x8 doses followed by 200 mg/m2

q 6 hours x4 dosesq 6 hours x4 doses1616

High dose did not compromise cureHigh dose did not compromise cure1616

HydrationHydration1010

2.5 -3.5 L/m2 per day starting 12 hours prior to MTX 2.5 -3.5 L/m2 per day starting 12 hours prior to MTX infusioninfusion

Urinary alkalinazationUrinary alkalinazation1010

50 mL of D5W containing sodium bicarbonate 1 mEq/kg 50 mL of D5W containing sodium bicarbonate 1 mEq/kg IV over 30 minutes q 4-6 hoursIV over 30 minutes q 4-6 hours

CytarabineCytarabine2020

MOA: primary action is inhibition of DNA MOA: primary action is inhibition of DNA polymerase resulting in decreased DNA polymerase resulting in decreased DNA synthesis and repair. synthesis and repair. Cytarabine is specific Cytarabine is specific for the S phase of the for the S phase of the cell cycle (blocks progression cell cycle (blocks progression from the G1 to the S phase).from the G1 to the S phase).

CytarabineCytarabine20,21,2220,21,22 Absorption: Complete with IVAbsorption: Complete with IV Distribution: Widely and rapidly in most tissuesDistribution: Widely and rapidly in most tissues

Crosses BBB with CSF levels of 40% to 50% of plasma Crosses BBB with CSF levels of 40% to 50% of plasma level level

Metabolism: Primarily hepatic; 86% to 96% of dose is Metabolism: Primarily hepatic; 86% to 96% of dose is metabolized to inactive metabolitemetabolized to inactive metabolite ITIT little conversion to inactive metabolite little conversion to inactive metabolite

Excretion: Renal (~80%; 90% as inactive metabolite) within 24 Excretion: Renal (~80%; 90% as inactive metabolite) within 24 hours hours

Half-lifeHalf-life IV: < 20 minutesIV: < 20 minutes2121

IT: 2-6 hours IT: 2-6 hours 20,2120,21

Cytarabine NeurotoxicityCytarabine Neurotoxicity13,21,2313,21,23

Route: Intrathecal, IV, liposomalRoute: Intrathecal, IV, liposomal23,1323,13

Cerebellar dysfunction (most common), generalized Cerebellar dysfunction (most common), generalized encephalopathy, peripheral neuropathy, and encephalopathy, peripheral neuropathy, and arachnoiditis, fecal and urinary incontinencearachnoiditis, fecal and urinary incontinence

Cytotoxic levels of cytarabine may be maintained for Cytotoxic levels of cytarabine may be maintained for up to 24 hours after IT administrationup to 24 hours after IT administration

IT liposomal (sustained release) may maintain IT liposomal (sustained release) may maintain cytotoxic concentrations of the drug in the CSF for up cytotoxic concentrations of the drug in the CSF for up to 14 daysto 14 days CSF exposure up to 40x that of standard Ara-CCSF exposure up to 40x that of standard Ara-C

Onset: As early as 2-5 days after treatmentOnset: As early as 2-5 days after treatment1313

May resolve spontaneously within a few days or May resolve spontaneously within a few days or may be permanentmay be permanent23,1323,13

Cytarabine NeurotoxicityCytarabine Neurotoxicity13,2313,23

Incidence: varies from 5-50%Incidence: varies from 5-50%13,2413,24

Risk factorsRisk factors13,2313,23

IV doses > 1 g/m2 IV doses > 1 g/m2 2323

Total IV dose > 30 g (Total IV dose > 30 g (>> 3g/ m2 every 12 hours) 3g/ m2 every 12 hours)33

IT dose (> 100 mg per week)IT dose (> 100 mg per week)2121

Age > 40 years of ageAge > 40 years of age1313

Prior cytarabine therapyPrior cytarabine therapy Renal dysfunctionRenal dysfunction IT, IT liposomal administrationIT, IT liposomal administration1313

Concomitant use with high-dose chemotherapy Concomitant use with high-dose chemotherapy (i.e. methotrexate)(i.e. methotrexate)13,2413,24

Cytarabine NeurotoxicityCytarabine Neurotoxicity25,2625,26

MOA of how it causes encephalopathy:MOA of how it causes encephalopathy:

-Cytotoxic effect-Cytotoxic effect2525

-Immune-mediated mechanism is hypothesized-Immune-mediated mechanism is hypothesized2626

Management:Management: Cytarabine should be discontinued immediatelyCytarabine should be discontinued immediately1313

No standard treatment is availableNo standard treatment is available Corticosteroids (methylprednisolone, Corticosteroids (methylprednisolone,

dexamethasone)dexamethasone)25,2625,26

PreventionPrevention Concurrent use of corticosteroid with IT liposomal Concurrent use of corticosteroid with IT liposomal

cytarabine reduces risk of arachnoiditiscytarabine reduces risk of arachnoiditis21,24,2521,24,25

RituximabRituximab2727

MOA: B cell lysis by binding of the Fab domain MOA: B cell lysis by binding of the Fab domain of rituximab to the CD20 antigen on B of rituximab to the CD20 antigen on B lymphocytes and by recruitment of immune lymphocytes and by recruitment of immune effector functions by the Fc domaineffector functions by the Fc domain Complement-dependent Complement-dependent

cytotoxicity (CDC)cytotoxicity (CDC) Antibody-dependent cellular Antibody-dependent cellular

cytotoxicity (ADCC)cytotoxicity (ADCC)

RituximabRituximab27,28,2927,28,29

Absorption: I.V.: Immediate and results in a rapid Absorption: I.V.: Immediate and results in a rapid and sustained depletion of circulating and and sustained depletion of circulating and tissue-based B cellstissue-based B cells

Metabolism: HepaticMetabolism: Hepatic Distribution: Lymph nodes Distribution: Lymph nodes Excretion: Uncertain; may undergo phagocytosis Excretion: Uncertain; may undergo phagocytosis

and catabolism in the reticuloendothelial system and catabolism in the reticuloendothelial system (RES)(RES)

Median terminal half-life for NHL: 22 days Median terminal half-life for NHL: 22 days (range: 6-52 days)(range: 6-52 days)

Rituximab NeurotoxicityRituximab Neurotoxicity3030

Progressive Multifocal Leukoencephalopathy Progressive Multifocal Leukoencephalopathy (PML)(PML)

Incidence: RareIncidence: Rare 2 PML cases per 8000 rituximab treated SLE 2 PML cases per 8000 rituximab treated SLE

patientspatients Need to conduct more epidemiological studiesNeed to conduct more epidemiological studies

Risk factors:Risk factors: Need more studiesNeed more studies Possibly low CD4 counts and low IgG levelsPossibly low CD4 counts and low IgG levels

Rituximab NeurotoxicityRituximab Neurotoxicity27,3027,30

Clinical presentationClinical presentation Confusion/disorientationConfusion/disorientation Motor weakness/hemiparesisMotor weakness/hemiparesis Altered vision/speechAltered vision/speech Poor motor coordination Poor motor coordination Symptoms progress over weeks to monthsSymptoms progress over weeks to months

MOA of how it causes encephalopathyMOA of how it causes encephalopathy1,21,2

Unclear, but rituximab can decrease the immune Unclear, but rituximab can decrease the immune system and cause reactivation of the Jakob-system and cause reactivation of the Jakob-Creuzfeld (JC) virusCreuzfeld (JC) virus


A retrospective analysis of patients diagnosed with PML A retrospective analysis of patients diagnosed with PML after rituximab treatmentafter rituximab treatment Cases from cancer centers or academic hospitals (22), Cases from cancer centers or academic hospitals (22),

FDA reports (11), manufacturers database (30), FDA reports (11), manufacturers database (30), publications (18)publications (18)

Inclusion: rituximab therapy prior to PML, PML Inclusion: rituximab therapy prior to PML, PML confirmation with brain histology or MRI, no HIV infectionconfirmation with brain histology or MRI, no HIV infection

Patient Population (n=57)Patient Population (n=57) B-cell lymphoproliferative disorder (52)B-cell lymphoproliferative disorder (52) Systemic Lupus Erythmetous (2)Systemic Lupus Erythmetous (2) Autoimmune pancytopenia (2)Autoimmune pancytopenia (2) Immune thrombocytopenia purpura (1)Immune thrombocytopenia purpura (1)


Onset:Onset: Median of 16 months (following rituximab Median of 16 months (following rituximab

initiation)initiation) 5.5 months (following last rituximab dose)5.5 months (following last rituximab dose) 6 rituximab doses preceded PML diagnosis6 rituximab doses preceded PML diagnosis

In the absence of immune reconstitution, case In the absence of immune reconstitution, case fatality rate was 90%fatality rate was 90% Survival rates up to 38% after hematopoietic Survival rates up to 38% after hematopoietic

stem cell transplantationstem cell transplantation

Rituximab NeurotoxicityRituximab Neurotoxicity27,3027,30

Promptly evaluate any patient presenting with Promptly evaluate any patient presenting with neurological changesneurological changes

Consider neurology consultation, brain MRI Consider neurology consultation, brain MRI and lumbar puncture for suspected PMand lumbar puncture for suspected PM LL

Discontinue rituximab in patients who Discontinue rituximab in patients who develop PMLdevelop PML

Consider reduction/discontinuation of Consider reduction/discontinuation of concurrent chemotherapy or concurrent chemotherapy or immunosuppressantsimmunosuppressants

Risks versus benefitsRisks versus benefits

Back to N.B.Back to N.B.

Clinical HistoryClinical History 6/16: confusion is clinically improving6/16: confusion is clinically improving 6/17: mental status seems to be slowly 6/17: mental status seems to be slowly

improvingimproving 6/20: confusion clinically stable6/20: confusion clinically stable

Acute altered mental status attributed to Acute altered mental status attributed to tacrolimus CNS toxicitytacrolimus CNS toxicity

Future DirectionsFuture Directions

Need of biological markers or markers for Need of biological markers or markers for quantification of medication-induced quantification of medication-induced neurotoxicityneurotoxicity AdenosineAdenosine Choline (higher levels correlated with Choline (higher levels correlated with

demyelination)demyelination) PatternsPatterns

MRI, CT, EEGMRI, CT, EEG

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