Pocket Oncology (Pocket Notebook Series), 1st Ed.

ALKYLATING AGENTS

Brian M. Seyboth

Busulfan (Busulfex [IV], Myleran [PO])

Dosing/dose adjustments: 1.8 mg/m2/d PO (adjust for goal leukocyte counts ≥15000/mm3) OR 120 mg/m2/d IV divided every 6–24 h over 3–4 d; dose per IBW or ABW (lower value) or adjusted BW (obesity); adjust dose per PK & target AUC (∼1200 μM × min [900–1500 μM × min])

PK/PD: PO bioavailability ∼80% (variable/age dependent), penetrates BBB, hepatic metabolism, T1/2 2.5 h

Adverse effects: Myelosuppression (DLT), hepatic VOD (↑ risk w/AUC >1500 μM × min), mucositis, seizure, pulm fibrosis (rare)

DDI: Glutathione depleting substrates (APAP, MNZ; ↑ busulfan conc.), azole antifungals (↓ busulfan conc.)

Clinical pearls: Administer w/ppx anticonvulsant (levetiracetam, phenytoin). Monitor signs of hepatic VOD (wt gain, ascites, ↑ Tbili, hepatomegaly).

Thiotepa

Dosing/dose adjustments: 0.3–0.4 mg/kg IV every 1–4 wks OR 150–250 mg/m2/dose IV divided 1–2 daily × 3 d before HSCT OR 60 mg instilled via intravesical administration weekly × 4 wks OR 10 mg IT 1–2 weekly or monthly. Consider dose reduction for renal or hepatic impairment or hematologic tox.

PK/PD: Hepatically metabolized via CYP2B6 & 2C11 to 1° metabolite TEPA, both thiotepa & TEPA therapeutically active & renally eliminated, T1/2 1.2–2 h; TEPA 3–21 h

Adverse effects: Myelosuppression (nadir: 2–3 wks), CNS dysfunction, amenorrhea, spermatogenesis inhibition, alopecia, 2° malignancies

DDI: Potent CYP2B6 inhibitor

Clinical pearls: Tight dressings & ointments should be avoided as thiotepa is excreted in sweat. Pt should shower often to reduce risk of skin irritation.

Bendamustine (Treanda)

Dosing/dose adjustments: 70–120 mg/m2/d IV × 2 d every 21–35 d. Renal: CrCl <40 mL/min: Not recommended. Hepatic: Mild impairment: Use w/caution; AST or ALT ≥2.5 times ULN or Tbili ≥1.5 times ULN: Not recommended. Tox ≥ grade 3: Reduce dose.

PK/PD: 94–96% protein bound, hepatic metabolism via CYP1A2, fecal excretion, T1/2 = ∼40 min; metabolites 30 min–3 h

Adverse effects: Myelosuppression (DLT; nadir: ~3 wks), N/V (mod. emetogenic risk), fever, ↑ bili, peripheral edema, rash, diarrhea, HSR

DDI: CYP1A2 inhibitors (amiodarone, ciprofloxacin, fluvoxamine; ↑ bendamustine), CYP1A2 inducers (carbamazepine, phenobarbital, rifampin; ↓ bendamustine)

Clinical pearls: Allopurinol may ↑ skin tox risk. Premedicate w/prior HSR ≤ grade 2 (antihistamines, antipyretics, corticosteroids)

Chlorambucil (Leukeran)

Dosing/dose adjustments: 0.1–0.2 mg/kg/d PO × 3–6 wks or 0.4 mg/kg PO intermittently, biweekly, or monthly. Consider dose reduction w/renal impairment or hematologic tox. No hepatic dose adjustments recommended.

PK/PD: Rapid, complete absorption, highly protein bound (99%), hepatic metabolism to active compound & renal excretion, T1/2 1.5 h

Adverse effects: Myelosuppression (nadir: 3 wks), hepatotoxicity, skin rxns, pulm tox, CNS disturbances, 2° malignancies

DDI: No significant drug interactions

Cyclophosphamide (Cytoxan)

Dosing/dose adjustments: 1–5 mg/kg/d PO OR 75–100 mg/m2/d PO × 14 d every 4 wks OR 250–1800 mg/m2/dose IV × 1–4 d every 3–4 wks OR 40–50 mg/kg/d IV. Consider dose adjustment w/renal & hepatic impairment.

PK/PD: PO bioavailability >75%, prodrug hepatically activated via CYP2B6, 3A4, & 2C9 (metabolites reduce glutathione), renal excretion, T1/2 3–12 h

Adverse effects: Myelosuppression (DLT; recovery: 7–10 d), hemorrhagic cystitis, nephrotoxicity, N/V (very high [>1500 mg/m2], mod. [≤1500 mg/m2 or PO] emetogenic risk), cardiotoxicity, alopecia, sterility, 2° malignancies

DDI: CYP3A4 inducers (phenobarbital, phenytoin, carbamazepine; ↑ cyclophosphamide metabolism to active metabolites), CYP3A4 inhibitors (aprepitant, azole antifungals; ↓ cyclophosphamide metabolism)

Clinical pearls: Properly hydrate pt pre/post-tx. Hemorrhagic cystitis due to accumulation of acrolein in the bladder, can be prevented w/MESNA (cum. dose 60–100% of cyclophosphamide dose)

Ifosfamide (Ifex)

Dosing/dose adjustments: 1200–3000 mg/m2/d IV × 3–5 d every 2–3 wks OR 5000 mg/m2 IV every 2 wks. Consider dose reduction w/renal or hepatic impairment.

PK/PD: Prodrug hepatically activated via CYP3A4 & 2A6, renal excretion, T1/2 7–15 h

Adverse effects: Myelosuppression (DLT; nadir 8–14 d), hemorrhagic cystitis, nephrotoxicity (proximal tubular damage), reversible neurotoxicity (somnolence, disorientation, lethargy), N/V (high [≥2 g/m2], mod. [<2 g/m2] emetogenic risk), alopecia.

DDI: CYP3A4 inducers/inhibitors (↑/↓ metabolism to active metabolites)

Clinical pearls: Properly hydrate pt pre/post-tx. Hemorrhagic cystitis due to accumulation of acrolein in the bladder, can be prevented w/MESNA (cum. dose 60–100% of ifosfamide dose). Neurotoxicity due to an accumulation of chloroacetaldehyde, can be treated w/methylene blue or thiamine.

Mechlorethamine (Mustargen)

Dosing/dose adjustments: 0.1–0.4 mg/kg/d IV × 1–4 d OR 6 mg/m2 IV on d 1, 8 in a 28-d cycle. No renal or hepatic dose adjustments recommended.

PK/PD: Rapid spontaneous hydrolysis w/in plasma & limited hepatic metabolism, renal excretion, T1/2 < 1 min

Adverse effects: Myelosuppression, N/V (high emetogenic risk), anticholinergic effects (diaphoresis, lacrimation, diarrhea), encephalopathy (high dose tx), gonadal atrophy, alopecia, 2° malignancies

DDI: No significant drug interactions

Clinical pearls: Causes irritation to skin/mucous membranes if contact occurs. Limited stability in solution & must be administered w/in an hour of preparation. Vesicant (treat w/sodium thiosulfate).

Melphalan (Alkeran)

Dosing/dose adjustments: 2–10 mg PO daily OR <0.05–0.15 mg/kg PO daily OR 0.2–0.25 mg/kg/d PO × 4–5 d every 4–6 wks OR 4–9 mg/m2/d PO × 4–7 d every 4–6 wks OR 16 mg/m2 IV × 4 doses every 2–4 wks OR 30 mg/m2IV × 1 dose (mini-BEAM) OR 140–200 mg/m2 once 2–5 d prior to HSCT. Renal: Mod. /sev. renal impairment: Reduce PO dose; BUN ≥ 30 mg/dL: Reduce IV dose by up to 50%. Consider reduction w/cell count tox.

PK/PD: Variable bioavailability (25–90%) & protein binding (53–92%), spontaneous hydrolysis or alkylation in plasma or tissues, renal excretion (20–30%), T1/2 1–2 h

Adverse effects: Delayed myelosuppression (nadir: 4 wks), mucositis, esophagitis, diarrhea, pulm fibrosis (chronic use), 2° malignancies

DDI: Carmustine (↑ risk of lung tox)

Clinical pearls: Limited stability in solution & must be administered w/in an hour of preparation. Improved bioavailability when taken on an empty stomach. Cryotherapy during infusion can ↓ mucositis.

Carmustine, BCNU (BiCNU, Gliadel [implantable wafer])

Dosing/dose adjustments: 150–200 mg/m2 IV every 6–8 wks OR 75–100 mg/m2/d IV × 2–3 d every 6–8 wks OR 300 mg/m2 IV 6 d (BEAM regimen). Consider reduced dose for renal impairment & hematologic tox.

PK/PD: ∼80% protein bound, penetrates BBB, hepatic metabolism, renal excretion, T1/2 < 30 min; active metabolite 67 h

Adverse effects: Delayed myelosuppression (DLT; nadir: 4–6 wks), N/V (high [>250 mg/m2], mod. [≤250 mg/m2] emetogenic risk), HoTN, ↑ LFTs. Cum. doses >1500 mg/m2- renal failure, pulm fibrosis.

DDI: Melphalan (sensitize pts to lung tox)

Clinical pearls: Evaluate renal function when cum. doses >1000 mg/m2. Chronic marrow hypoplasia may result after repeated dosing. A/w 2° malignancies.

Lomustine, CCNU (CeeNU)

Dosing/dose adjustments: 100–130 mg/m2 PO every 6 wks. Consider dose reduction for renal impairment or prior cell count nadir.

PK/PD: Complete absorption, penetrates BBB, hepatic metabolism to active metabolites, renal excretion, T1/2 16–24 h; active metabolite 16–48 h

Adverse effects: Delayed myelosuppression (DLT; nadir: 4–6 wks), N/V, ↑ LFTs, 2° malignancies, cum. doses >1500 mg/m2 a/w renal failure, pulm fibrosis less frequent than w/carmustine

DDI: No significant drug interactions

Clinical pearls: Evaluate renal function when cum. doses >1000 mg/m2. Chronic marrow hypoplasia may result after repeated dosing. Pts should take on an empty stomach to ↓ N/V.

Carboplatin (Paraplatin)

Dosing/dose adjustments: 300–400 mg/m2 IV every 4 wks. Often dosed per Calvert formula: Total dose = Target AUC × (GFR + 25). Common target AUC 3–7.5 every 3–4 wks or AUC 2 for 3–5 d per month. Renal (nonCalvert dosing): CrCl 41–59: 250 mg/m2; CrCl 16–40: 200 mg/m2. Thrombocytopenia/neutropenia: 75% of dose.

PK/PD: Renal excretion, T1/2 ∼2–6 h (platinum ≥5 d)

Adverse effects: Delayed myelosuppression (DLT; nadir: ~3–6 wks), HSR, nephrotoxicity, ototoxicity, peripheral neuropathy, N/V (mod. emetogenic risk), electrolyte imbalance, ↑ LFTs

DDI: Sorafenib (↑ carboplatin tox), topotecan (↑ topotecan tox)

Clinical pearls: Cap GFR at 125 mL/min in Calvert formula

Cisplatin (Platinol)

Dosing/dose adjustments: 20–100 mg/m2/d IV × 1–5 d every 3–4 wks. SCr >1.5 mg/dL or BUN >25 mg/dL: Do not use. Consider dose reduction for renal impairment.

PK/PD: Highly protein bound (>90%), nonenzymatic metabolism, renal excretion (>90%), T1/2 < 1 h; protein bound platinum 1–5 d

Adverse effects: Nephrotoxicity, N/V acute/delayed 2–5 d post dose (DLT; high [≥50 mg/m2], mod. [<50 mg/m2] emetogenic risk), peripheral neuropathy (cum. dose 300–600 mg/m2; reversible), ototoxicity & hearing loss (cum. dose >400 mg/m2; irreversible), electrolyte disturbance, Raynaud phenomenon, HSR, ↑ LFTs

DDI: AG (↑ nephrotoxicity), loop diuretics (↑ nephrotoxicity & ototoxicity), phenytoin (↓ phenytoin conc.), topotecan (↑ topotecan tox), vinorelbine (granulocytopenia)

Clinical pearls: Properly hydrate pt pre/post-tx. Mannitol can be used to ↑ UOP. Antiemetic Rx must cover delayed N/V period. Monitor renal function, electrolytes, & signs of hearing loss & neuropathy frequently. Vesicant (at conc. >0.5 mg/mL).

Oxaliplatin (Eloxatin)

Dosing/dose adjustments: 85–130 mg/m2 IV every 2–3 wks. Renal: CrCl < 30 mL/min: Reduce dose to 65 mg/m2. Reduce dose for prolonged neuropathy, & grade 3–4 GI & cell count tox.

PK/PD: Highly protein bound (>90%), hydrolyzed to reactive metabolites, renal excretion, T1/2 391 h (platinum metabolites)

Adverse effects: Neurotoxicity (DLT), myelosuppression, pharyngolaryngeal dysesthesia, peripheral neuropathy, ↑ LFTs, ↑ SCr, fever

DDI: No significant drug interactions

Clinical pearls: Cold temperatures can worsen peripheral neuropathy

Dacarbazine (DTIC-Dome)

Dosing/dose adjustments: 250 mg/m2/d IV × 4–5 d every 3 wks OR 375 mg/m2/dose IV on d 1, 15 every 4 wks (ABVD regimen). Consider dose adjustment w/renal impairment.

PK/PD: Prodrug hepatically activated via CYP1A2, minimally bound to protein (∼5%), renal excretion, T1/2 40 min; active metabolite 5 h

Adverse effects: N/V (DLT but can become tolerant; high emetogenic risk), mild myelosuppression, flu-like sx, injection site pain

DDI: CYP1A2 inducers (↑/↓ conversion to active metabolites)

Procarbazine (Matulane)

Dosing/dose adjustments: 1–6 mg/kg/d PO. Consider dose reduction for hepatic impairment.

PK/PD: Rapid & complete absorption, prodrug hepatically activated, penetrates BBB, renal excretion of metabolites, T1/2 10 min

Adverse effects: Myelosuppression, N/V (mod. -high emetogenic risk), paresthesias, somnolence, depression, agitation, azoospermia, ovarian failure, 2° malignancies

DDI: Alpha/Beta agonists (↑ BP), antihypertensive (↓ BP), antidepressants, antipsychotics, carbamazepine, cyclobenzaprine, linezolid, methadone, tramadol (serotonergic effect), hypoglycemic agents (hypoglycemic effect). Many medications interact w/MAO inhibitors, review medication list before starting procarbazine.

Clinical pearls: As a MAO inhibitor, pts should avoid foods high in tyramine. EtOH should be avoided due to disulfiram rxn.

Temozolomide (Temodar)

Dosing/dose adjustments: 100–200 mg/m2/d IV or PO × 5–7 d every 14–28 d OR 75 mg/m2/d IV or PO × 6 wks. Consider dose reduction for renal impairment or nonhematologic tox ≥ grade 3.

PK/PD: Rapid & complete absorption, prodrug spontaneously hydrolyzed to active metabolite in plasma, penetrates BBB, renal excretion (∼38%), T1/2 1.8 h; active metabolite 2.5 min

Adverse effects: Myelosuppression (DLT; nadir: 21 d), N/V (mod. -high emetogenic risk), HA, fatigue, constipation, ↑ LFTs, peripheral edema, seizure, alopecia, muscle pain, vision changes

DDI: No significant drug interactions

Clinical pearls: PO form should be administered consistently on either an empty stomach or w/food, as food will affect bioavailability

Info. based on publicly available drug inserts from ESP Pharma, Inc., GlaxoSmithKline LLC, Bedford Laboratories, Cephalon, Inc., Baxter Healthcare Corporation, Lundbeck LLC, Apo-Pharma USA, Inc., E.R. Squibb & Sons, L.L.C., Teva Parenteral Medicines, Inc., Sanofi-aventis U.S. LLC, Sigma-Tau Pharmaceuticals, Inc., & Merck Sharp & Dohme Corp.