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 7th ed. McGraw-Hill; 2008:2332.
2
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 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
7
Cytotoxic Agents
 Alkylating agents
•
•
•
•
•
•
Cyclophosphamide
Busulfan
Melphalan
Carmustine
Carboplatin
Thiotepa
 Antimetabolites
• Cytarabine
• Fludarabine
 Topoisomerase II
inhibitors
• Etoposide
8
NonMyeloa
bl.
Myeloablative
Common Conditioning
Regimens
Name
HSCT/Dx
BEAM: carmustine (BCNU), etoposide, cytarabine
(Ara-C), melphalan
Auto HD
BuCy (busulfan, cyclophosphamide)
Allo/Auto
Heme
BuFlu (busulfan, fludarabine)
Allo Heme
Cyclophosphamide + ATG
Allo
Aplastic Anemia
Melphalan
Auto
Multiple Myeloma
Carboplatin + Etoposide
Germ cell cancer
Cyclophosphamide + Fludarabine
Allo MDS, HD
Fludarabine + Melphalan
Allo Heme
9
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 AGENTS
Cyclophosphamide
Busulfan
Melphalan
Carmustine
Carboplatin
Thiotepa
13
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
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
over
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, 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.;2008
Lacy 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.;2008
Lacy 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_Q24IV_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.;2008
Lacy 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.;2008
Lacy 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 bilirubin
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)
 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
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, 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.;2008
Lacy 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
28
ANTIMETABOLITES
Cytarabine
Fludarabine
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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.;2008
Lacy 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.;2008
Lacy 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.;2008
Lacy 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.;2008
Lacy CF, et al. DIH, 20th ed. Lexi-Comp, Inc.;2011
33
TOPOISOMERASE II INHIBITORS
Etoposide
34
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.;2008
Lacy 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.;2008
Lacy CF, et al. Drug Information Handbook, 20th ed. Hudson, OH: Lexi-Comp, Inc.;2011
37
NonMyeloa
bl.
Myeloablative
Common Conditioning
Regimens
Name
HSCT/Dx
BEAM: carmustine (BCNU), etoposide, cytarabine
(Ara-C), melphalan
Auto HD
BuCy (busulfan, cyclophosphamide)
Allo/Auto
Heme
BuFlu (busulfan, fludarabine)
Allo Heme
Cyclophosphamide + ATG
Allo
Aplastic Anemia
Melphalan
Auto
Multiple Myeloma
Carboplatin + Etoposide
Germ cell cancer
Cyclophosphamide + Fludarabine
Allo MDS, HD
Fludarabine + Melphalan
Allo Heme
38
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
BONE MARROW TRANSPLANT
CHEMOTHERAPY
Jenny Li, Pharm.D.
PGY2 Oncology Pharmacy Resident
Wednesday, November 9, 2011