BONE MARROW TRANSPLANT BONE MARROW TRANSPLANT CHEMOTHERAPYCHEMOTHERAPY

Jenny Li, Pharm.D.PGY2 Oncology Pharmacy Resident

Wednesday, November 9, 2011

High Dose Therapy Rationale

DiPiro JT, et al. Pharmacotherapy 7DiPiro JT, et al. Pharmacotherapy 7 thth ed. McGraw-Hill; 2008:2332. ed. McGraw-Hill; 2008:2332. 22

Conditioning Regimens

Myeloablative

Nonmyeloablative

Radiotherapy/immunosuppression

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Myeloablative Conditioning

Eliminate cancer in malignant disease

Make space for donor stem cells

Suppress recipient immune system from stem cell rejection in allo-SCT

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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

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Non-Myeloablative Conditioning

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

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

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Cytotoxic Agents

Alkylating agents• Cyclophosphamide• Busulfan• Melphalan• Carmustine• Carboplatin• Thiotepa

Antimetabolites• Cytarabine• Fludarabine

Topoisomerase II inhibitors• Etoposide

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Common Conditioning Regimens

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Cell-Cycle Activity of Cytotoxic Agents

DiPiro JT, et al. Pharmacotherapy 7th ed. McGraw-Hill; 2008:2094. 10

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 AGENTSALKYLATING AGENTSCyclophosphamide

BusulfanMelphalan

CarmustineCarboplatin

Thiotepa13

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.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. DIH, 20th 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/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.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. DIH, 20th 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. 21

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.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011 23

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 bilirubinChu E, DeVita VT. Physicians’ Cancer Chemotherapy. Jones and Bartlett Pub.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011 26

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.;2008Lacy CF, et al. DIH, 20th 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

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ANTIMETABOLITESANTIMETABOLITES

CytarabineFludarabine

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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.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011 31

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.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011 33

TOPOISOMERASE II TOPOISOMERASE II INHIBITORSINHIBITORS

Etoposide

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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/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.;2008Lacy CF, et al. DIH, 20th 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.;2008Lacy CF, et al. Drug Information Handbook, 20th ed. Hudson, OH: Lexi-Comp, Inc.;2011 37

Common Conditioning Regimens

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Dose-Limiting Toxicities

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

Non-Hematologic Dose Limiting ToxicitiesBusulfan: hepatotoxicity; GI; pulmonaryCarmustine: pulmonary; hepatotoxicityCyclophosphamide: cardiotoxicityMelphalan: mucositis; GIThiotepa: neurotoxicity; mucositisCarboplatin: nephrotoxicity

Fludarabine: neurotoxicity

Etoposide: mucositis; GI

Total body irradiation: pulmonary toxicity; GI

BONE MARROW TRANSPLANT BONE MARROW TRANSPLANT CHEMOTHERAPYCHEMOTHERAPY

Jenny Li, Pharm.D.PGY2 Oncology Pharmacy Resident

Wednesday, November 9, 2011