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Alkylating agents

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dina salah

on 26 May 2013

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Transcript of Alkylating agents

Place your own picture
behind this frame! Double click to crop it if necessary (cc) photo by Metro Centric on Flickr (cc) photo by Franco Folini on Flickr (cc) photo by jimmyharris on Flickr (cc) photo by Metro Centric on Flickr (cc) photo by Metro Centric on Flickr (cc) photo by Franco Folini on Flickr (cc) photo by jimmyharris on Flickr (cc) photo by Metro Centric on Flickr (cc) photo by Metro Centric on Flickr (cc) photo by Franco Folini on Flickr (cc) photo by jimmyharris on Flickr (cc) photo by Metro Centric on Flickr Alkylating Agents Nitrogen mustard Mechlorethamine
(Mustargen) MOA:
it is a prototype alkylating agent.
Its action involves transfer of the alkyl group to amino Carboxyl,hydroxyl,imidazole,phosphate&sulfhydryl groups
Within the cell,altering structure & function of DNA(primarily)
RNA &proteins. 1ry indications:
Hodgkin's lymphoma(MOPP) &non-Hodgkins Lymphoma.
Usual dosage &schedule : 6 mg/m2IV on days 1 &8 every 4 weeks
(in MOPP regimen) Dose adjustment:
•If leukocytes 2-<3 administer 50% of the dose.
•If platelets (50 -100) & leukocytes <2 administer 25% of the dose Special precautions:
adminster as slow IV push over few minutes into ! sidearm of a free flowing IV line, taking care to avoid extravasation.

Bec mechlorethamine is a potent vesicant, extreme care must be exercised while preparing & adminstering the drug. If accidental skin contact occurs, irrigate ! affected part immediately with water for at least 15 min & follow by sodium thiosulfate solution (1/6 M) which is the treatment of extravasation. It is prepared as follows : 4 ml 10% sodium thiosulfate mixed with 6 ml water for injection (1/6M) solution injected SQ around extravasation site.

Also DMSO (50-99%) used for extravasation.

mechlorethamine should be used soon after preparation (15-30 min) as it decomposes on standing.

It must not be mixed in! Same syringe with any other drug. Toxicity:
1-myelosuppression: DLT,with ! nadir at approximately
1 week & recovery with 3 weeks.

2- acute N&V

3- severe painful inflamation & necrosis are likely if
extra vasations occurs.

4-miscellaneous effects
•Phlebitis, thrombosis, or both
•Amenorrhea & azospermia (gonadal dysfunction)
•Hyperuricemia
•Secondary neoplasms Monitoring:
CBC with differential, Hg & platelet count Cyclophosphamide
(cytoxan) Broadest spectrumof nitogen mustards.
Prodrug must be activated in the liver to active metabolites. MOA:
•Metabolism of cyclophosphamide by hepatic microsomal
enzymes produces active metabolites.
•Primary effect of cyclophosphamide is probably on DNA. 1ry indications:
•Hodgkin's disease,Non-Hodgkin's lymphoma, Sclc
•In high doses (2gm/m2) for BMT. Dosage adjustment:
Crcl <25 decrease dose by 25%. Special precautions:
Administer in the a.m. & advise the patient to drink
3 liters of fluid a day with frequent urination. Toxicity:
• Myelosuppression (DLT)
• Delayed N & V.
• Haemorrhagic cystitis.
• Reversible alopecia.
• Hyperuricemia.
• Interstitial pneumonitis & pulmonary fibrosis. Drug-drug interaction:
•With methotrexate cause inhibition of metabolism of cyclophosphamide Monitoring:
• CBC with differential, Platelet count , ESR, BUN Serum electrolytes & serum creatinine
• Urinalysis (RBCS ) for high IV dose >1gm/m2 Resistance:
•Altered drug metabolism
•Increase GSH
increase detoxification of cell converting it to inactive agent. Ifosfamide
(Ifex) Analogue of cyclophosphamide
1ry indication:
• Relapsed testicular cancer, Soft tissue sarcoma
Cancers of lung , breast & ovary Dosage adjustment:
Bilirubin 2-4 75% of the dose
>4 discontinue
Crcl 40-60 75%
20-40 50%
<20 discontinue Special precautions:
•Must use with MESNA to prevent hemorrhagic cystitis
Short infusion of MESNA is dosed as 20 % of ifosfamide dose immediately before & then 4&8 hours after IV boluses of ifosfamide.
•Vigorous hydration with 1.5 to 2 liters of NS pre & posthydration
Encourage patient to increase oral fluid intake to 2-3 liters of fluid/day Toxicity:
Myelosuppression
Hemorrhagic cystitis (DLT)
Alopecia
Miscellaneous effects:
•CNS toxicity
•Infertility
•Renal impairment is occasional to common
•Fanconi syndrome dependant on dose
•May be severe acidosis Interactions:
Bolus dose of MESNA before
+4, +8 with aprepitant cause neurotoxicity. Monitoring:
Urinalysis for RBCS MELPHALAN
(alkeran) Dosage & adm:
• Oral & IV dosing schedule
Variable oral absorption, especially when taken with food so take on empty stomach. Special precautions:
•Myelosuppression may be delayed & prolonged to 4-6 weeks.
Reduce IV dose by 50% for cr>1.5×ULN.
•Use in early myeloma may preclude harvest of sufficient
numbers of peripheral stem for autologous transplantation. Toxicity:
•Myelosuppression (DLT)
•N& V common with high dose regimen
•Hypersensitivity
•Extravasation so it is taken IV slow push through sidearm of free flowing IV line
•Alopecia& mucositis are common on high-dose regimen
•Gonadal dysfunction Monitoring Parameters:

CBC with differential and platelet count
serum electrolytes
serum uric acid. Chlorambucil
(leukaran) Dosage adjustment
severe myelosuppression discontinue special precautions:
• should not be used with in 4 weeks of full course of RT Toxicity:
Myelosuppression (DLT)
Miscellaneous effects:
•Amenorrhea & azospermia are common
•Hyperuricemia
•Pulmonary fibrosis is rare
•CNS effects including seizure & coma may
be seen at very high doses (>100 mg/m2) Monitoring: Lab Tests
Liver function tests
CBC with differential and platelets
(weekly, with WBC monitored twice
weekly during the first 3-6 weeks of treatment)
serum uric acid Bendamustine
(Treanda) MOA:
Bendamustine is an alkylating agent (nitrogen mustard derivative) with a benzimidazole ring (purine analog) which demonstrates only partial cross-resistance (in vitro) with other alkylating agents.
It leads to cell death via single and double strand DNA cross-linking.
Bendamustine is active against quiescent and dividing cells. The primary cytotoxic activity is due to bendamustine (as compared to metabolites). 1ry indication
•Treatment of chronic lymphocytic leukemia (CLL);
treatment of progressed indolent B-cell
non-Hodgkin’s lymphoma (NHL) Toxicity:
•Peripheral edema
•Rash
•Dehydration
•N&V, D
•constipation
•anorexia
•weight loss
•stomatitis •abdominal pain
•appetite loss
•Myelosuppression
(nadir: in week 3)
•Lymphopenia
•anemia
•thrombocytopenia
•neutropenia
•Bilirubin increased Dosage adjustment
Hepatic impairment: Use with caution in patients with mild hepatic impairment. Use is not recommended in patients with moderate (AST or ALT 2.5-10 times ULN and total bilirubin 1.5-3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment.
Renal impairment: Use with caution in patients with mild-to-moderate renal impairment. Use is not recommended in patient with Clcr <40 mL/minute.
Severe or progressive cuteneous reaction: discontinue Monitoring Parameters
CBC with differential (monitored weekly [initially] in clinical trials)
serum creatinine (pretreatment)
ALT, AST, and total bilirubin MOA:
•Cross linking of DNA.
•Interfering with DNA replication & transcription. 1ry indications:
•MM,breast & ovarian cancer
•Stem cell preparative regimens MOA:
• Interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA 1ry indications:
•CLL,Hodgkin's & non-Hodgkin's lymphoma, ovarian & breast cancer. Usual dosage & schedule:
•3-4 mg/m2 po daily until a response is seen or cytopenias occur, then if necessary,maintain with 1-2 mg/m2 po daily.
•30 mg/m2 po once every 2 weeks (with or without prednisone 80 mg/m2 po on days 1-5). Nitrosureas Carmustine
(BiCNU; Gliadel Wafer) MOA:
Interferes with the normal function of DNA and RNA by alkylation and cross-linking the strands of DNA and RNA, and by possible protein modification; may also inhibit enzyme processes by carbamylation of amino acids in protein. Dosage adjustment:
1-Renal Impairment
• Clcr 46-60 mL/minute: Administer 80% of dose
• Clcr 31-45 mL/minute: Administer 75% of dose
• Clcr ≤30 mL/minute: Consider use of alternative drug.
2-Bone marrow suppression (thrombocytopenia, leukopenia) is the major toxicity and may be delayed; monitor blood counts weekly for at least 6 weeks after administration. Toxicity:
A-systemic therapy
• Myelosuppression (cumulative, dose related, delayed, and dose limiting)
•Severe N&V, Burning (with skin contact), hyperpigmentation of skin (with skin contact) & Hypotension (with high-dose I.V. therapy, due to the alcohol content of the diluent)
•Interstitial fibrosis occurs in up to 50% of patients B- implantable carmustine-impregnated wafer
•Limited toxicity beyond that expected from craniotomy is seen. Serious intracranial infection was seen in 4 % of pts, compared with 1% of placebo-treated pts.
• Brain edema not responsive to steroids may also be seen in a similar % of pts.
•Abnormal wound healing may occur.
•Remnants of this wafer may be seen for many months after implantation. Monitoring Parameters
•CBC with differential and platelet count,
pulmonary function, liver function, and renal function tests;
monitor blood pressure during administration. Lomustine
(CCNU.CeeNU) 1ry indications:
1-Systemic therapy
Primary brain cancer :iv
Hodgkin's & non-Hodgkin's lymphomas
Autologous BMT: iv
2-implantable carmustine-impregnated wafer
Glioblastoma multiforme (recurrent), malignant glioma MOA:
• Inhibits DNA and RNA synthesis via carbamylation of DNA polymerase, alkylation of DNA, and alteration of RNA, proteins, and enzymes 1ry indication:
•Brain tumors Usual dosage & schedule
• Oral: 130 mg/m2 as a single dose once every 6 weeks on empty stomach (dosage reductions may be recommended for combination chemotherapy regimens)
• Compromised marrow function: Reduce dose to 100 mg/m2 as a single dose once every 6 weeks Dosing adjustment:
Renal Impairment
•Clcr 10-50 mL/minute: Administer 75% of dose
•Clcr <10 mL/minute: Administer 25% to 50% of dose Special precautions:
Do not administer courses more frequently than every 6 weeks due to delayed myelotoxicity. Use with caution in patients with depressed platelet, leukocyte or erythrocyte counts. Because bone marrow toxicity is cumulative; dose adjustments should be based on nadir counts from prior dose. Toxicity:
1-Hematologic: Myelosuppression (dose-limiting, delayed, cumulative); leukopenia (65%; nadir: 5-6 weeks; recovery 6-8 weeks); thrombocytopenia (nadir: 4 weeks; recovery 5-6 weeks)
2-Gastrointestinal: Nausea and vomiting, (onset: 3-6 hours after oral administration; duration: <24 hours)
3-Stomatitis & alopecia are rare 4-Miscellaneous effects:
confusion ,lethargy & ataxia are rare
2ry neoplasia is possible
pulmonary fibrosis is uncommon at doses of less than 1.000 mg/m2
renal toxicity is uncommon at doses of less than 1.000mg/m2 Monitoring Parameters:
•CBC with differential and platelet count (for at least 6 weeks after dose), hepatic and renal function tests (periodic), pulmonary function tests (baseline and periodic) Triazenes Dacarbazine
(DTIC-DOME) Dacarbazine is a prodrug that is activated by cyp450 system as well as photodecomposition MOA:
Dacarbazine is an alkylating agent. It is converted to the active alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide].

The cytotoxic effects of MTIC are manifested through alkylation of DNA at the O6, N7 guanine positions which appears to attack cross-links strands of DNA resulting in the inhibition of DNA, RNA, and protein synthesis. 1ry indication
Hodgkin's disease (combination chemotherapy)
Metastatic melanoma
Soft tissue sarcoma Usual dose & schedule:
Hodgkin's disease (combination chemotherapy): I.V.: 375 mg/m2/dose days 1 and 15 every 4 weeks (ABVD regimen)

Metastatic melanoma: I.V.: 250 mg/m2/dose days 1-5 every 3 weeks Dose adjustment:
Renal impairment
• Clcr 46-60 mL/minute: Administer 80% of dose
• Clcr 31-45 mL/minute: Administer 75% of dose
• Clcr <30 mL/minute: Administer 70% of dose Special precautions:
Adminster cautiously to avoid extravasation as tissue damage may occur.

Venous pain along! injection site may be reduced by diluting dacarbazine in 100-200 ml of 5% dextrose in water & infusing over 30 min rather than injecting rapidly.

Ice application may also reduce pain. Toxicity
Hematologic: Myelosuppression (onset: 5-7 days; nadir: 7-10 days; recovery: 21-28 days), leukopenia, thrombocytopenia.

Gastrointestinal: Nausea and vomiting (>90%) highly emetogenic, anorexia.

Dermatologic: Alopecia

Local: Pain on infusion Miscellaneous effects:
flu-like syndrome (fever, myalgia, malaise)

facial flushing.

hepatotoxicity:hepatic necrosis, hepatic vein occlusion, liver enzymes increased (transient) Monitoring Parameters:

CBC with differential
liver function Temozolamide
(Temodar) MOA:
Like dacarbazine, temozolomide (a prodrug) is rapidly and nonenzymatically converted to the active alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide].

Unlike dacarbazine, however, this conversion is spontaneous, nonenzymatic, and occurs under physiologic conditions in all tissues to which it distributes.

The cytotoxic effects of MTIC are manifested through alkylation of DNA at the O6, N7 guanine positions. 1ry indication:
Glioblastoma multiforme (newly diagnosed, high-grade glioma):

a-Concomitant phase: 75 mg/m2/day for 42 days with focal radiotherapy

b-Maintenance phase (consists of 6 treatment cycles): Begin 4 weeks after concomitant phase completion.

Anaplastic astrocytoma that is refractory to nitrosoureas. Usual dosing & schedule
Oral dose taken on empty stomach

Anaplastic astrocytoma (refractory): Oral, I.V.: Initial dose: 150 mg/m2/day for 5 days; repeat every 28 days. Subsequent doses of 100-200 mg/m2/day for 5 days per treatment cycle; based upon hematologic tolerance.

Glioblastoma multiforme

Concomitant phase: 75 mg/m2/day for 42 days with focal radiotherapy (60Gy administered in 30 fractions). Dose adjustment:
Anaplastic astrocytoma (refractory): ANC <1000/mm3 or platelets <50,000/mm3 on day 22 or day 29 (day 1 of next cycle): Postpone therapy until ANC >1500/mm3 and platelets >100,000/mm3; reduce dose by 50 mg/m2/day for subsequent cycle

Glioblastoma multiforme

ANC 500/mm3 but <1500/mm3 or platelet count 10,000/mm3 but <100,000/mm3 orgrade 2 nonhematologic toxicity (excludes alopecia, nausea/vomiting): Interrupt therapy

ANC <500/mm3 or platelet count <10,000/mm3 or grade 3/4 nonhematologic toxicity (excludes alopecia, nausea/vomiting): Discontinue therapy Special precautions:

Contraindicated in pts with hypersensitivity (eg, allergic reaction, anaphylaxis, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis) to temozolomide or any component of the formulation; hypersensitivity to dacarbazine (both drugs are metabolized to MTIC)

Pneumonia: Pneumocystis jiroveci pneumonia (PCP) may occur; risk is increased in those receiving steroids or longer dosing regimens; PCP prophylaxis is required in patients receiving radiotherapy in combination with the 42-day temozolomide regimen. Toxicity:

Myelosuppression
N&V
Alopecia &rash Miscellaneous effects:
CNS: Fatigue , headache , seizure , fever , dizziness

CVS: Peripheral edema

Neurologic symptoms are common on temozolamide but it is difficult to distinguish whether symptoms from the drug or the disease common findings are convulsions,hemiparesis dizziness,abnormal coordination& insomnia

Occasional findings are paresthesias, somnolence,paresis,incontinence, diplopia or other visual abnormalities

Anxiety & depression are occasional Monitoring Parameters:

CBC with differential and platelets (prior to each cycle; weekly during glioma concomitant phase treatment; at or within 48 hours of day 22 and weekly until ANC >1500/mm3 for glioma maintenance and astrocytoma treatment) Platinum
analogues Cisplatin
(CDDP,DDP, PLATINOL) MOA:
Inhibits DNA synthesis by the formation of DNA cross-links; denatures the double helix; covalently binds to DNA bases and disrupts DNA function; may also bind to proteins; the cis-isomer is 14 times more cytotoxic than the trans-isomer; both forms cross-link DNA but cis-platinum is less easily recognized by cell enzymes and, therefore, not repaired.

Cisplatin can also bind two adjacent guanines on the same strand of DNA producing intrastrand cross-linking and breakage. 1ry indications:

Advanced bladder cancer
Metastatic ovarian cancer
Metastatic testicular cancer Usual dosage & schedule
40-120 mg/m2 IV on day 1 as infusion every 3 weeks.
15-20 mg/m2 IV on days 1-5 as infusion every 3-4 weeks Dose adjustment:

Renal Impairment:
Clcr 10-50 mL/minute: Administer 75% of dose
Clcr <10 mL/minute: Administer 50% of dose OR consider use of alternative drug Special precautions:

Do not administer if serum creatinine level> 1.5 mg/dl

Irreversible renal tubular damage may occur if vigorous diuresis is not maintained , particularly with higher doses (>40 mg/m2 ) & with additional concurrent nephrotoxic drugs such as aminoglycosides

Hydration: Patients should receive adequate hydration, with or without diuretics, prior to and for 24 hours after administration; serum electrolytes, particularly magnesium and potassium, should be monitored and replaced as needed during and after therapy.

Extravasation happens so tt with 1/3 or 1/6 Na thiosulphate Toxicity:

Renal: Nephrotoxicity (acute renal failure and chronic renal insufficiency)
GIT: N/V acute & delayed

Hematologic: Myelosuppression mild to moderate depending on dose

CNS: Neurotoxicity: Peripheral neuropathy is dose- and duration-dependent.
Otic: Ototoxicity VOD in conventional doses

Arrhythmias Severe electrolyte abnormalities: hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia,

anaphylactic reaction
Monitoring Parameters:

Renal function (serum creatinine, BUN, Clcr)
electrolytes (particularly magnesium, calcium, potassium) before and within 48 hours after cisplatin therapy
audiography (baseline and prior to each subsequent dose)
neurologic exam (with high dose)
liver function tests periodically
CBC with differential and platelet count
urine output, urinalysis CARBOPLATIN
(Paraplatin) Usual dose & schedule:
calculated by the target AUC using the Calvert formula, where Total dose (mg) = Target AUC x (GFR +25)
target AUC is commonly from4-8depending on previous tt & other drugs to be used
adm dose is given by IV infusion over 15-60 min & repeated every 4 weeks Dose adjustment:

Renal Impairment:

Baseline Clcr 41-59 mL/minute: Initiate at 250 mg/m2 and adjust subsequent doses based on bone marrow toxicity
Baseline Clcr 16-40 mL/minute: Initiate at 200 mg/m2 and adjust subsequent doses based on bone marrow toxicity special precautions:

Anaphylactic reactions: [U.S. Boxed Warning]: Anaphylactic-like reactions have been reported with carboplatin; may occur within minutes of administration.
Epinephrine, corticosteroids and antihistamines have been used to treat symptoms. The risk of allergic reactions (including anaphylaxis) is increased in patients previously exposed to platinum therapy.
Skin testing and desensitization protocols have been reported
Much less renal toxicity than cisplatin, no need for vigorous hydration Toxicity

Hematologic: Myelosuppression (dose related and dose limiting; nadir at ~21 days; recovery by ~28 days),thrombocytopenia

GIT: Vomiting , abdominal pain , nausea (without vomiting: 10% to 15%) Renal: Creatinine clearance decreased , BUN increased Hepatic: Alkaline phosphatase increased , AST increased, VOD in conventional doses Miscellaneous effects

Decreased incidence of nephrotoxicity ,ototoxicity ,N& V
Hypersensitivity/allergic reaction are uncommonely seen with rash ,pruritus & rarely bronchospasm& hypotension as infusion reactions
Monitoring Parameters:

CBC (with differential and platelet count)
serum electrolytes
serum creatinine and BUN
creatinine clearance
liver function tests Oxaliplatin
(Eloxatin) 1ry indication
Advanced colorectal cancer
Esophageal/gastric cancers Dose adjustment:

Acute toxicities: Longer infusion times (up to 6 hours) may mitigate acute toxicities

Neurosensory events:
Persistent (>7 days) grade 2 neurosensory events: Consider oxaliplatin dose reduction if symptoms do not resolve:
Adjuvant treatment of stage III colon cancer: Reduce dose to 75 mg/m2
Advanced colorectal cancer: Reduce dose to 65 mg/m2
Consider withholding oxaliplatin for grade 2 neuropathy lasting >7 days despite dose reduction.
Persistent grade 3 neurosensory events: Consider discontinuing oxaliplatin Renal Impairment: Use in patients with Clcr <30 mL/minute is contraindicated Special precautions:

Extravasation Risk: Cool compress may be used for immediate management of extravasation, with consideration of potential for peripheral neuropathy exacerbated by cold.
Do not prepare using a chloride-containing solution such asNacl Neuropathy:
Two different types of peripheral sensory neuropathy may occur: First, an acute (within first 2 days), reversible (resolves within 14 days), with primarily peripheral symptoms that are often exacerbated by cold (may include pharyngolaryngeal dysesthesia); avoid mucositis prophylaxis with ice chips during oxaliplatin infusion; may recur with subsequent doses.

Secondly, a more persistent (>14 days) presentation that often interferes with daily activities (eg, writing, buttoning, swallowing), these symptoms may improve in some patients upon discontinuing treatment. Toxicity
Neuromuscular & skeletal: Peripheral neuropathy (may be dose limiting
GIT: N/v, diarrhea , abdominal pain, constipation , anorexia , stomatitis
Hematologic: Anemia , thrombocytopenia , leukopenia
Hepatic: AST increased , ALT increased , total bilirubin increased
Minimal nephrotoxicity & ototoxicity Monitoring Parameters
CBC with differential
blood chemistries (including serum creatinine, ALT, AST, and bilirubin)
INR and prothrombin time (in patients on oral anticoagulant therapy)
signs of neuropathy, hypersensitivity, and/or respiratory effects Ethylenimines Thiotepa
(thioplex) MOA:
Alkylating agent that reacts with DNA phosphate groups to produce cross-linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis. 1ry indication:
Leukemia
Hodgkin’s disease
Bladder cancer
Ovarian &breast cancer
Effusions Usual dose & schedule:

Bladder cancer: Intravesical: 60 mg in 30-60 mL NS retained for 2 hours once weekly for 4 weeks

Ovarian, breast cancer: I.V.: 0.3-0.4 mg/kg by rapid I.V. administration every 1-4 weeks

Effusions: Intracavitary: 0.6-0.8 mg/kg Special precautions
Renal Impairment:
Use with extreme caution, reduced dose may be warranted.
Use may be contraindicated with existing renal impairment and should be limited to cases where benefit outweighs risk. Toxicity
Myelosuppression (DLT)
Hyperpigmentation of skin occurs at high doses Miscellaneous effects:

dizziness, fatigue, fever, headache are uncommon
2ry neoplasms are possible
Amenorrhea & azospermia are common
CNS effects with high dose therapy
Rash Monitoring Parameters

CBC with differential and platelet count (monitor weekly during treatment and for at least 3 weeks after treatment)
Renal and liver function tests; uric acid, urinalysis Alkyl sulfonates Busulfan
(myleran, Busulfex) MOA:
Busulfan is an alkylating agent which reacts with the N-7 position of guanosine and interferes with DNA replication and transcription of RNA.

Busulfan has a more marked effect on myeloid cells than on lymphoid cells and is also very toxic to hematopoietic stem cells. Busulfan exhibits little immunosuppressive activity.

Interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA. 1ry indication
CML remission, induction: standard doses
BMT marrow-ablative conditioning regimen Usual dosage & schedule
CML remission induction: Oral: 60 mcg/kg/day or 1.8 mg/m2/day; usual range: 4-8 mg/day (may be as high as 12 mg/day); Maintenance doses: 1-4 mg/day to 2 mg/week to maintain WBC 10,000-20,000 cells/mm3

BMT marrow-ablative conditioning regimen

Oral: 1 mg/kg/dose (ideal body weight) every 6 hours for 16 doses

I.V.: 0.8 mg/kg (ideal body weight or actual body weight, whichever is lower); for obese or severely-obese patients adjusted ideal body weight is recommended) every 6 hours for 4 days (a total of 16 doses)

High-dose therapy requires pretreatment with phenytoin Special precautions

Obtain CBC weekly while pt is on therapy.

If leukocyte count falls rapidly to less than 15.000/ul, discontinue therapy until nadir is reached & rising counts indicate a need for further treatment. Toxicity
Hematologic: Myelosuppression (≤100%), neutropenia (100%; median recovery: 13 days), thrombocytopenia (98%; median onset: 5-6 days), lymphopenia (children: 79%), anemia (69%)
Dermatologic: Hyperpigmentation of skin occurs occasionally
N&V rare
Metabolic effects: adrenal insufficiency is rare hyperuricemia may occur when! Leukemia cell count is rapidly reduced.
Ovarian suppression & amenorrhea are common
gynecomestia Miscellaneous effects
2ry neoplasia is possible

Hepatic: Hyperbilirubinemia , ALT increased , veno-occlusive disease with high dose, jaundice

Seizures after high dose therapy are occasion Monitoring Parameters
CBC with differential and platelet count
liver function tests (evaluate transaminases, alkaline phosphatase, and bilirubin daily for at least 28 days post transplant) By: Yousra Salah
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