Page 1027 - Hematology_ Basic Principles and Practice ( PDFDrive )

910 Part VII Hematologic Malignancies

dose-limiting toxic effect. Febrile reactions, which occur a few hours insulin with hyperglycemia; and decreased serum lipoproteins. In
after bleomycin administration and may last 4–12 hours, are also 25% or fewer of patients, cerebral dysfunction, characterized by
common. Fever becomes less frequent with continued use of the drug confusion, stupor, and frank coma, can occur. Although the neuro-
and can usually be prevented by concurrent administration of gluco- toxic effects resemble those of ammonia toxicity, they are apparently
corticosteroids (e.g., 100 mg of hydrocortisone). Bleomycin has vir- caused by low concentrations of either L-asparagine or L-glutamine
tually no myelosuppressive effect. Anaphylactoid reactions are in the brain. Acute pancreatitis, which may progress to severe hemor-
observed in approximately 1% (up to 8% in some series) of patients rhagic pancreatitis, may occur in 15% of patients. Elevation of liver
with lymphomas treated with bleomycin. enzymes and serum bilirubin is almost universal and is histologically
represented by fatty metamorphosis. Liver toxicity, although usually
Potential Drug Interaction: Bleomycin, administered with other not clinically significant, has resulted in occasional fatalities. Aspara-
drugs for the treatment of lymphorrhea, can decrease the oral bio- ginase can occasionally produce renal functional impairment with
availability of digoxin and the pharmacologic effect of phenytoin and oliguric renal failure.
certain anesthetic drugs.
Potential Drug Interactions: When asparaginase is administered
Therapeutic Indications in Hematology: Bleomycin is often immediately before or concurrent with methotrexate, it decreases the
incorporated in the chemotherapy regimens of Hodgkin lymphoma cytotoxic effect of the latter. When administered to patients with
(ABVD and MOPP-ABV hybrid regimens) and NHL (MACOP-B, acute leukemia 9–10 days before or shortly after methotrexate,
PROMACE-CYTABOM, M-BACOD, and CHOP-Bleo). however, asparaginase appears to enhance the cytotoxic effect of
methotrexate. Concurrent administration of asparaginase with vin-
Asparaginase cristine may increase vincristine’s neurotoxic effects, but this effect
appears to be less pronounced when asparaginase is given after vin-
Chemistry and Mechanism of Action: Asparaginase contains cristine. The effects of asparaginase on liver function may potentially
the high-molecular-weight enzyme L-asparaginase amidohydrolase, interfere with the activation or metabolism of other cytotoxic agents.
type EC-2, derived from Escherichia coli. Asparaginase hydrolyzes
serum asparagine to nonfunctional aspartic acid and ammonia, Therapeutic Indications in Hematology: Asparaginase is used
depriving tumor cells of a required amino acid; thus, tumor cell in combination therapy for remission induction of ALL.
proliferation is blocked by the interruption of asparagine-dependent
protein synthesis. The drug appears to be most active in the G 1 phase. Glucocorticoids

Absorption, Fate, and Excretion: Asparaginase is not absorbed Chemistry and Mechanism of Action: Glucocorticoids are
orally. Its plasma half-life varies from 8 to 30 hours and is not synthetic compounds derived from the natural adrenal hormone
influenced by dosage, age, sex, surface area, or renal or hepatic cortisol. Glucocorticoids mediate their biologic actions predomi-
function. nantly by binding to their cytosolic receptor, which then translocates
to the nucleus. There, as a homodimer, it binds to specific DNA
Preparation and Administration: Asparaginase is commercially sequences located in the regulatory regions of a number of genes.
available in vials containing 10,000 IU of asparaginase in 80 mg Gene transcription can be upregulated or downregulated by gluco-
of mannitol. For IV use, the drug should be reconstituted with corticoids. They can also inhibit binding of the AP-1 transcription
5 mL of either sterile water or sodium chloride for injection and factor to its DNA consensus sequence site. Lymphocytes treated with
injected in the tubing of a freely running infusion of either normal glucocorticoids undergo apoptosis mediated by glucocorticoid recep-
saline or 5% dextrose in water over 30 minutes. For IM or SC use, tors. An early cytostatic phase is marked by growth inhibition and
each vial should be reconstituted with 2 mL of sodium chloride cessation of proliferation caused by inhibition of cellular uptake of
for injection to obtain a 5000-U/mL solution. For dosages that glucose, amino acids, and nucleosides, as well as inhibition of mac-
exceed 2 mL, use of two injection sites is recommended. For both romolecular synthesis. This is followed by a cytolytic phase character-
IV and IM administration, the drug must be used within 8 hours ized by chromatin condensation and internucleosomal DNA
of reconstitution, and only if it is clear. Because of the possibility of cleavage.
HSRs (particularly in patients with lymphomas), an intradermal skin
test is recommended before initial administration of asparaginase or Absorption, Fate, and Excretion: Many synthetic glucocorti-
when 1 week has elapsed between doses. For this test, 2 IU should coids are available, the three most commonly used in hematology
be injected intradermally and observed for a wheal or erythema being prednisone, dexamethasone, and methylprednisolone. Gluco-
for 1 hour. A negative skin test result, however, does not preclude corticoids are well absorbed orally and are primarily metabolized in
possible development of a HSR. It is recommended that oxygen, the liver. Unlike the other two glucocorticoids, the activity of pred-
epinephrine, and corticosteroids be available at the bedside during nisone depends on hepatic conversion to the 11-hydroxy form
administration of the drug. For allergic patients, the E. coli form of (prednisolone). Whereas the biologic half-lives of prednisone and
asparaginase should be replaced by the asparaginase derived from methylprednisolone are approximately 12–36 hours, dexamethasone
Erwinia carotovora, provided by the NCI as an investigational group has a biologic half-life of 36–72 hours. Plasma half-lives for all three
C agent. drugs are within the range of 3–4 hours. Compared with cortisol, the
relative antiinflammatory potencies of dexamethasone, methyl-
Toxic Effects: The toxicity of asparaginase is reported to be greater prednisolone, and prednisone are 25, 5, and 4, respectively, for
in adults than in children. Anorexia, nausea, or vomiting occurs in equivalent doses.
approximately one-third of patients. Most of the other side effects
can be divided into two main groups, those related to HSRs to the Preparation and Administration: Prednisone is available only
foreign protein and those resulting from decreased protein synthesis. for oral administration, but methylprednisolone and dexamethasone
The HSR is characterized by urticaria, laryngeal edema, broncho- are available in oral and parenteral dosage forms.
spasm, or hypotension and may occur with the initial dose of the
drug even if the skin test result is negative. More commonly, however, Toxic Effects: When glucocorticoids are used for less than 14 days,
allergic phenomena are observed after multiple courses of treatment. as is often done when they are used in combination with other
Adverse effects related to the inhibition of protein synthesis include cytotoxic agents, the most common side effects include euphoria,
hypoalbuminemia and decreases in serum fibrinogen, prothrombin, insomnia, psychosis, hyperglycemia, hypokalemia, increased appetite,
antithrombin III, and other coagulation factors, which may lead to metabolic alkalosis, proximal muscular weakness, and fluid retention
both clotting and hemorrhagic complications; decreased serum with edema formation and hypertension. When used on a chronic