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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 Medicine Rotation City of Hope Outline Patient case Background of encephalopathy Causes of encephalopathy in HSCT recipients Drug-induced encephalopathy Tacrolimus Methotrexate Cytarabine Rituximab Future directions Questions 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 Case: N.B. 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. 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. 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. 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 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 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 MOA: potent inhibition on T-lymphocyte activation by inhibiting calcineurin phosphatase activity 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 (<2% as unchanged drug) Biological half-life varies: 3.5-40.5 hours3 Tacrolimus Neurotoxicity 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 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 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 Methotrexate9,10 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 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 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 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 Route (IV, IT) and dose-dependent (cumulative exposure) 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 IV > 1 g/m2 (or frequent IV)12,16,18 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 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 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). 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: < 20 minutes21 IT: 2-6 hours 20,21 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 Cytarabine Neurotoxicity13,23 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 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 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 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 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 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 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 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 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. 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 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