Page 1004 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 887

leukemia are potential risks of prolonged therapy. Rare cases of pul- Preparation and Administration: Carmustine is commercially
monary fibrosis have also been reported. available in 100-mg vials as a white lyophilized powder. The
drug is reconstituted with 3 mL of absolute alcohol provided by
Potential Drug Interactions: None reported. the manufacturer and 27 mL of sterile water, and can be further
diluted with normal saline or 5% dextrose in water. It should be
Therapeutic Indications in Hematology: The major uses are used immediately after reconstitution and can be infused over
in the treatment of Waldenström macroglobulinemia, low-grade 1–2 hours.
lymphomas, chronic lymphocytic leukemia (CLL), and Hodgkin Carmustine is chemically stable for 3 hours at room temperature
lymphoma. Except for CLL, chlorambucil has been supplanted by and for 24 hours when refrigerated.
newer agents.
Toxic Effects: Myelosuppression is the dose-limiting toxic effect
Busulfan (Myleran) and tends to increase with successive cycles of therapy. Leukopenia
and thrombocytopenia are characteristically delayed and reach their
Chemistry: Busulfan is an alkylsulfonate bifunctional alkylating maximum between the third and sixth weeks after drug administra-
agent not chemically related to mechlorethamine. It forms DNA tion. Nausea and vomiting can be severe. Abnormal liver function
intrastrand and interstrand cross-links. test results may be found, but the abnormalities are usually mild and
reversible. Two rare but serious toxic effects include cumulative
Absorption, Fate, and Excretion: Busulfan is well absorbed pulmonary or interstitial pneumonitis progressing to fibrosis and
after oral administration. When given by the IV route, greater than progressive renal damage, which are dose related. Secondary leuke-
90% is cleared from the plasma after 3 minutes. The drug is exten- mias can also occur 5–10 years after treatment. Patients who receive
2
sively metabolized to inactive compounds that are excreted renally. greater than 1100 mg/m are at increased risk of pulmonary fibrosis.
The major metabolite is methane sulfonic acid, although more than Carmustine is not a vesicant, but rapid infusion often produces a
10 other not fully identified metabolites exist. Virtually no intact burning sensation at the injection site.
busulfan is found in the urine. The biologic half-life of busulfan is
approximately 2.5 hours. Potential Drug Interactions: Cimetidine may enhance the
myelosuppressive effect of carmustine. Carmustine may decrease the
Preparation and Administration: The drug is commercially pharmacologic effects of phenytoin. In rats with intracerebrally
available as 2-mg tablets. implanted tumors, pretreatment with phenobarbital eliminated the
antitumor activity of carmustine. The reduction in carmustine anti-
Toxic Effects: Although at low doses the major effect of busulfan tumor activity correlated with increased carmustine metabolism,
is on the granulocytic series, at high doses all three hematologic series which is apparently the result of hepatic microsomal enzyme
are affected. Compared with the other alkylating agents, its nadir of induction.
myelosuppression may be relatively late, in a range of 11–30 days.
Hematologic recovery is also prolonged and may take approximately Therapeutic Indications in Hematology: Carmustine in
54 days. A relatively common side effect is an Addisonian-like syn- combination with other cytotoxic agents may be used in the initial
drome characterized by skin hyperpigmentation and weakness but treatment of Hodgkin lymphoma (BCVPP regimen) and multiple
without abnormalities in adrenal function. Cumulative pulmonary myeloma (VBAP regimen). In high-dose therapy, it appears in BEP
toxicity has been well described and consists of a mixed alveolar and for relapsed lymphomas.
interstitial pneumonitis. As with the other alkylating agents, infertil-
ity and leukemogenesis can occur. Nausea and vomiting are rare. At Lomustine (CCNU)
high doses, it is associated with hepatic venoocclusive disease in up
to 19% of patients. Seizures may also occur and are controlled by Chemistry: Lomustine, also called CCNU, is a nitrosourea deriva-
diphenylhydration. tive with choloroethyl and cyclohexyl side chains.
Potential Drug Interactions: A metabolic interaction may take Absorption, Fate, and Excretion: The drug is rapidly absorbed
place between busulfan and various anticonvulsant medications; from the gastrointestinal tract and is rapidly and completely metabo-
however, further description of the specific effects is awaited. lized. Its active metabolites have prolonged plasma half-lives, within
a range of 16–48 hours. Approximately 50% of an administered dose
Therapeutic Indications in Hematology: Busulfan is used is detectable (as metabolites) in the urine within 24 hours, and 75%
mainly in the treatment of chronic myeloid leukemia. More recently, is detectable within 4 days. Active metabolites cross the blood–brain
high-dose busulfan has been incorporated into preparatory regimens barrier and can be detected in significant concentrations in the
for bone marrow transplantation. Blood level monitoring with adjust- cerebrospinal fluid.
ment for higher dose levels improved therapeutic outcome and
reduced toxicity. Preparation and Administration: The drug is commercially
available in 10-, 40-, and 100-mg capsules.
Carmustine (BCNU)
Toxic Effects: The toxicity profile of lomustine is similar to that
Chemistry: Carmustine, also called BCNU (1,3[bis]-2-chloroethyl- of carmustine. Because lomustine can produce vomiting and the drug
nitrosourea), decomposes spontaneously into a chloroethyl hydroxide is given orally, special attention should be directed to emesis control.
that can alkylate the DNA and into an isocyanide molecule, which If the patient vomits soon after ingestion, the vomitus should be
may produce carbamylation of proteins. Cytotoxicity is caused by inspected for the presence of intact capsules. The drug should be
DNA cross-links. given again if capsules are identified with certainty. Secondary leuke-
mias are reported 3–10 years after use.
Absorption, Fate, and Excretion: IV-administered carmustine
is rapidly metabolized, with a half-life of 70 minutes. Approximately Potential Drug Interactions: These are similar to those of
30%–80% of metabolites are eliminated in the urine within 24 carmustine.
hours. The drug, its metabolites, or both readily cross the blood–brain
barrier, resulting in cerebrospinal fluid concentrations within the Therapeutic Indications in Hematology: Lomustine is occa-
range of 15%–70% of plasma levels. Peak serum levels vary widely sionally used as second-line treatment for patients with Hodgkin
in patients treated at 200–600 mg IMF. lymphoma and NHL and for childhood gliomas.