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BONE MARROW TRANSPLANT CHEMOTHERAPY

BONE MARROW TRANSPLANT CHEMOTHERAPY. Jenny Li, Pharm.D. PGY2 Oncology Pharmacy Resident Wednesday, November 9, 2011. High Dose Therapy Rationale. DiPiro JT, et al. Pharmacotherapy 7 th ed. McGraw-Hill; 2008:2332. 2. Conditioning Regimens. Myeloablative Nonmyeloablative

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BONE MARROW TRANSPLANT CHEMOTHERAPY

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  1. BONE MARROW TRANSPLANT CHEMOTHERAPY Jenny Li, Pharm.D. PGY2 Oncology Pharmacy Resident Wednesday, November 9, 2011

  2. High Dose Therapy Rationale DiPiro JT, et al. Pharmacotherapy 7th ed. McGraw-Hill; 2008:2332. 2

  3. Conditioning Regimens • Myeloablative • Nonmyeloablative • Radiotherapy/immunosuppression 3

  4. Myeloablative Conditioning • Eliminate cancer in malignant disease • Make space for donor stem cells • Suppress recipient immune system from stem cell rejection in allo-SCT 4

  5. Non-Myeloablative Conditioning • Graft-versus-tumor effect (GVT) from donor T-cells • Reduced-intensity conditioning (RIC) regimens • No eradication of host hematopoiesis and reversible myelosuppression 5

  6. Non-Myeloablative Conditioning DiPiro JT, et al. Pharmacotherapy 7th ed. McGraw-Hill; 2008. 6

  7. Reduced Intensity Conditioning Regimen • Advantages • Decreased acute toxicity • Application to older and/or morbid patients • Disadvantages • Loss/decrease in anti-tumor activity from cytotoxic chemotherapy/radiation 7

  8. Alkylating agents Cyclophosphamide Busulfan Melphalan Carmustine Carboplatin Thiotepa Antimetabolites Cytarabine Fludarabine Topoisomerase II inhibitors Etoposide Cytotoxic Agents

  9. Common Conditioning Regimens

  10. Cell-Cycle Activity of Cytotoxic Agents DiPiro JT, et al. Pharmacotherapy 7th ed. McGraw-Hill; 2008:2094. 10

  11. Properties of DNA Image: US National Library of Medicine. Available at www.ghr.nlm.nih.gov. Accessed on 11/4/11.

  12. From DNA to Protein Image: Available at www.cytochemistry.net/cell-biology/ribosome.htm. Accessed on 11/4/11.

  13. ALKYLATING AGENTS Cyclophosphamide Busulfan Melphalan Carmustine Carboplatin Thiotepa

  14. Alkylating Agents • Evolved from mustard gas used in WWI • Vesicant on skin/mucous membranes • Affects eyes/respiratory tract • Mechanism • Crosslink DNA strands • Prevents cells from replicating • Toxicities • Myelosuppression (dose-limiting) • Nausea/vomiting • Sterility • Secondary malignancies Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008

  15. Cyclophosphamide • Dose 60mg/kg IV daily for 2 days • Activated by CYP450 to phosphoramide mustard and acrolein • Hemorrhagic cystitis 5-10% • Goal fluid intake >2-3L/day • Empty bladder several times daily (every 2 hours) • Uroprotection with mesna • 100% cyclophosphamide dose over 24h, start 1h before CTX Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  16. Hemorrhagic Cystitis Image: Takeuchi T, et al. Case Reports in Medicine 2010.

  17. Cyclophosphamide • Other toxicities • Alopecia • Skin/nail hyperpigmentation • Symptoms of inappropriate antidiuretic hormone (SIADH) • Rhinitis/irritation of nose/throat • Cardiotoxicity and rare CHF • Monitor • Renal function/output/signs of bleeding • Regimens: BuCy, CyATG, CyFlu Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  18. Nail Hyperpigmentation Images: www.accessmedicine.net and www.neurology.org. Accessed 11/4/11.

  19. Busulfan • Dose 0.8mg/kg IV every 6 hours for 16 doses • Infuse over 2 hours • Dose 130mg/m2 once daily for 4 doses • Infuse over 3 hours • Drug Interaction • APAP ↓busulfan metabolism & ↑toxicity • Give APAP > 72 hours before busulfan • Toxicity • ↑ seizures reported (10%; range 2-40%) • Seizure prophylaxis with levetiracetam or phenytoin • Start 24 hours before, continue 24-48 hours after Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  20. Busulfan • Other toxicities • Interstitial pulmonary fibrosis (busulfan lungs) • Other neurotoxicity (diziness, anxiety) • Skin/nail hyperpigmentation • Mucositis • Veno-occlusive disease • Monitor • Neurotoxicity (seizures, somnolence, lethargy confusion) • Monitor drug level based on AUC • Regimens: BuCy, BuFlu Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  21. Busulfan Monitoring • Goal AUC 900-1350 • Sample draw times for every 6 hour dosing • Sample #1 (at END of infusion) • Samples #2 & #3 (15 minutes apart from END of infusion) • Sample #4 (3 hours from START of infusion) • Sample #5 (4 hours from START) • Sample #6 (5 hours from START) • Sample #7 (6 hours from START) • Draw 1-3mL blood in heparinized tube (always iced) • Centrifuge , remove and freeze plasma in labeled tube • Send to lab in Seattle with dry ice • Dose adjustments made after 6th dose • For daily dosing, 6 draws needed, adjust after 3rd dose Seattle Cancer Care Alliance. Available at http://www.seattlecca.org/client/documents/Req_Q6-IV_Q24-IV_Busulfex_v2.pdf Accessed on 11/4/11.

  22. Melphalan • Dose 140-200mg/m2 IV over 15-20 minutes for 1 dose • Must be given within 30 minutes of mixing • Toxicity • Hypersensitivity 2-10% • Severe diarrhea, nausea, vomitting • Mucositis • Prophylaxis with cryotherapy • Shower twice daily Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  23. Melphalan • Monitor • GI toxicity • Hypersensitivity reactions • Bronchospasm, dyspnea, tachycardia, etc • Regimen: BEAM or by itself Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  24. Carmustine(BCNU) • Dose 300mg/m2 IV for 1 day • Toxicity • Cumulative pulmonary toxicity >500mg/m2 • Renal toxicity at doses >1000mg/m2 • Facial flushing/discoloration (hang over) • Contains 20% alcohol • Administer slowly over 1-2h • Hepatic toxicity with ↑LFT and bilirubin Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  25. Carmustine(BCNU) • Monitor • Infusion site reaction (burning, pain) • Dyspnea, cough, fever • Can occur 1-3 months post transplant • Regimen: BEAM Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  26. Thiotepa • Mainly pediatric regimens • Toxicities • Nausea/vomiting • Mucositis (dose-limiting) • Skin rash, erythema, hyperpigmentation • Neurotoxicity (confusion) Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  27. Carboplatin • Dosing AUC or mg/m2 • CrCl: [(140 – age) x ABW] / (72 x SCr)] x 0.85 if female • IBW: (2.3 x inches > 60”) + (45.5 if F / 50 if M) • AdjWt if ABW > 1.25 x IBW: [(ABW-IBW) x 0.4] + IBW • Calvert formula: • Total dose mg = target AUC x (GFR + 25) • Cap GFR = 125 ml/min • Toxicities • Nephrotoxicity (less than cisplatin) • Ototoxicity (less than cisplatin) • Mild nausea and vomitting • Neuropathy < 10% (less than oxaliplatin) Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  28. Carboplatin Example • 55 year old female • Weight = 90kg • Height = 65 inches • SCr = 1.2 • AUC = 5 • IBW = (2.3 x 5) + 45.5 = 57kg • CrCl = [(140-55) x 57kg] / (72 x 1.2)] x 0.85 • CrCl = 48ml/min • Dose = 5 x (48 + 25) = 365mg

  29. ANTIMETABOLITES Cytarabine Fludarabine

  30. Cytarabine(ARA-C) • Pyrimidine analog, incorporated into DNA leading to chain termination • Dose 100mg/m2 over 1 hour every 12 hours x 8 doses (BEAM) • FLAG 2000mg/m2 daily for 5 doses • Toxicities at low dose • Myelosuppression • Transient ↑liver enzymes • Mucositis • Diarrhea • Toxicities at high dose • Cytarabine syndrome (fever, myalgia, bone pain, rash) • Chemical conjunctivitis • Cerebellar toxicity (> 40 years, abrnomal renal/hepatic function) • Pulmonary toxicity (ARDS) Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  31. Cytarabine(ARA-C) • Other toxicities • Hepatic dysfunction • Acute pancreatitis • Hand-foot syndrome at high dose • Regimen: BEAM Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  32. Fludarabine • 5-monophosphate analog of cytarabine (prodrug) • Dose 20-40mg/m2 IV daily for 4 doses • Toxicities • T-cell depletion • PCP prophylaxis • Bactrim DS daily for three times weekly (MWF) • Antifungal prophylaxis (fluconazole) • Antiviral prophylaxis (acyclovir) Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  33. Fludarabine • Other toxicities • Autoimmune effects • Hemolytic anemia, thrombocytopenia • Fever, rash, hypersensitivity • Neurotoxicity (headache, solmnolence) • Peripheral neuropathy • Interstitial pneumonitis • Regimen: BuFlu, FluCy, FluTBI Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  34. TOPOISOMERASE II INHIBITORS Etoposide

  35. Topoisomerase II Inhibitors Figure: Froelich-Ammon SJ, et al. J BiolChem 1995;270:21429-32.

  36. Etoposide • Stabilizes topoisomerase II-DNA complex (prevents unwinding) • Dose 100-200mg/m2 IV over 60min every 12 hours for 8 doses • Watch for cracking of plastic/tubing • Toxicities • Anaphylaxis (polysorbate 80) • Infusion related reaction (↓BP, flushing) • Infuse over > 1 hour, slower infusion if occurs • Hypersensitivity: bronchospasm, chills • Mucositis, diarrhea Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011

  37. Etoposide • Other toxicities • Secondary malignancies • Metallic taste during transfusion • Administration • Maximum concentration = 0.4mg/mL • Monitor for precipitation • Formulation • Phosphate salt more soluble • Maximum concentration = 20mg/mL • Regimen: BEAM, Carboplatin + Etoposide Chu E, DeVita VT. Physicians’ Cancer Chemotherapy Drug Manual. Sudburry, MA: Jones and Bartlett Pub.;2008 Lacy CF, et al. Drug Information Handbook, 20th ed. Hudson, OH: Lexi-Comp, Inc.;2011

  38. Common Conditioning Regimens 38

  39. Dose-Limiting Toxicities Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH. Lexi-Comp, Inc.;2011

  40. BONE MARROW TRANSPLANT CHEMOTHERAPY Jenny Li, Pharm.D. PGY2 Oncology Pharmacy Resident Wednesday, November 9, 2011

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