Bone marrow transplant chemotherapy

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Transcript 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.

Conditioning Regimens

 Myeloablative  Nonmyeloablative  Radiotherapy/immunosuppression 3

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

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

Non-Myeloablative Conditioning

DiPiro JT, et al. Pharmacotherapy 7 th ed. McGraw-Hill; 2008.

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

Cytotoxic Agents

 Alkylating agents • • Cyclophosphamide Busulfan • Melphalan • Carmustine • Carboplatin • Thiotepa  Antimetabolites • • Cytarabine Fludarabine  Topoisomerase II inhibitors • Etoposide 8

Common Conditioning Regimens

Name

BEAM: carmustine (BCNU), etoposide, cytarabine (Ara-C), melphalan BuCy (busulfan, cyclophosphamide) BuFlu (busulfan, fludarabine)

HSCT/Dx

Auto HD Allo/Auto Heme Allo Heme Cyclophosphamide + ATG Melphalan Carboplatin + Etoposide Allo Aplastic Anemia Auto Multiple Myeloma Germ cell cancer . Cyclophosphamide + Fludarabine Fludarabine + Melphalan Allo MDS, HD Allo Heme 9

Cell-Cycle Activity of Cytotoxic Agents

DiPiro JT, et al. Pharmacotherapy 7 th ed. McGraw-Hill; 2008:2094.

Properties of DNA

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

From DNA to Protein

Image: Available at www.cytochemistry.net/cell-biology/ribosome.htm. Accessed on 11/4/11.

ALKYLATING AGENTS

Cyclophosphamide Busulfan Melphalan Carmustine Carboplatin Thiotepa

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 14

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, 20 th ed. Lexi-Comp, Inc.;2011 15

Hemorrhagic Cystitis

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

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, 20 th ed. Lexi-Comp, Inc.;2011 17

Nail Hyperpigmentation

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

Busulfan

 Dose 0.8mg/kg IV every 6 hours for 16 doses • Infuse over 2 hours  Dose 130mg/m 2 • 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, 20 th ed. Lexi-Comp, Inc.;2011 19

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, 20 th ed. Lexi-Comp, Inc.;2011 20

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.

Melphalan

 Dose 140-200mg/m 2 for 1 dose IV over 15-20 minutes  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, 20 th ed. Lexi-Comp, Inc.;2011 22

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, 20 th ed. Lexi-Comp, Inc.;2011 23

Carmustine (BCNU)

 Dose 300mg/m 2 IV for 1 day  Toxicity • Cumulative pulmonary toxicity >500mg/m 2 • Renal toxicity at doses >1000mg/m 2 • 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, 20 th ed. Lexi-Comp, Inc.;2011 24

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, 20 th ed. Lexi-Comp, Inc.;2011 25

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, 20 th ed. Lexi-Comp, Inc.;2011 26

Carboplatin

 Dosing AUC or mg/m 2 • 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, 20 th ed. Lexi-Comp, Inc.;2011 27

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 28

ANTIMETABOLITES

Cytarabine Fludarabine



Cytarabine (ARA-C)

Pyrimidine analog, incorporated into DNA leading to chain termination  Dose 100mg/m 2 • over 1 hour every 12 hours x 8 doses (BEAM) FLAG 2000mg/m 2 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, 20 th ed. Lexi-Comp, Inc.;2011 30

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, 20 th ed. Lexi-Comp, Inc.;2011 31

Fludarabine

 5-monophosphate analog of cytarabine (prodrug)  Dose 20-40mg/m 2 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, 20 th ed. Lexi-Comp, Inc.;2011 32

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, 20 th ed. Lexi-Comp, Inc.;2011 33

TOPOISOMERASE II INHIBITORS

Etoposide

Topoisomerase II Inhibitors

Figure: Froelich-Ammon SJ, et al. J Biol Chem 1995;270:21429-32.

Etoposide

 Stabilizes topoisomerase II-DNA complex (prevents unwinding)  Dose 100-200mg/m 2 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, 20 th ed. Lexi-Comp, Inc.;2011 36

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, 20 th ed. Hudson, OH: Lexi-Comp, Inc.;2011 37

Common Conditioning Regimens

Name

BEAM: carmustine (BCNU), etoposide, cytarabine (Ara-C), melphalan BuCy (busulfan, cyclophosphamide) BuFlu (busulfan, fludarabine)

HSCT/Dx

Dose-Limiting Toxicities

Non-Hematologic Dose Limiting Toxicities

Busulfan: hepatotoxicity; GI; pulmonary Carmustine: pulmonary; hepatotoxicity Cyclophosphamide: cardiotoxicity Melphalan: mucositis; GI Thiotepa: neurotoxicity; mucositis Carboplatin: nephrotoxicity Fludarabine: neurotoxicity Etoposide: mucositis; GI Total body irradiation: pulmonary toxicity; GI Chu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008 Lacy CF, et al. DIH. Lexi-Comp, Inc.;2011 39