Page 1011 - Hematology_ Basic Principles and Practice ( PDFDrive )

894 Part VII Hematologic Malignancies

Preparation and Administration: Hydroxyurea is provided as rarely, if ever, been seen in patients receiving conventional doses (e.g.,
2
500-mg capsules. The drug is stored at room temperature in tightly 25 mg/m /day for 5 days). Rare reports of interstitial pneumonitis
capped containers and protected from heat. have appeared.
Toxic Effects: The most common adverse reactions include Potential Drug Interactions: Fludarabine has been shown to
myelosuppression (leukopenia, thrombocytopenia, anemia), gastro- potentiate the intracellular metabolism and activity of ara-C, although
intestinal symptoms (e.g., nausea and vomiting, stomatitis, anorexia, the toxicity of this combination may also be enhanced. No other
appetite disturbances), and dermatologic toxicity (e.g., rashes, skin interactions have been reported.
ulcerations, facial erythema). Rarer toxicities, generally seen at high
doses include neurologic disturbances, such as drowsiness, dizziness, Therapeutic Indications in Hematology: Fludarabine has
headache, and convulsions; altered renal function; and alopecia. The shown marked activity in both untreated CLL and in disease refrac-
mutagenic potential of hydroxyurea is unknown, and the drug should tory to standard alkylating agent therapy. Fludarabine has also shown
be avoided when possible in pregnant women. activity as a single agent, and particularly in combination with others
(e.g., mitoxantrone, Cytoxan) in indolent NHL.
Potential Drug Interactions: As noted earlier, hydroxyurea may
increase the toxicity of certain nucleoside analogs. Hydroxyurea may 2′-Chlorodeoxyadenosine
also serve as a radiosensitizing agent; consequently, patients receiving
concurrent radiation therapy may experience enhanced toxicity. Chemistry and Mechanism of Action: 2′-Chlorodeoxy-
adenosine (CdA; cladribine) is a derivative of deoxyadenosine that
Therapeutic Indications in Hematology: Hydroxyurea has differs from its parent compound by the presence of a chlorine moiety
also been successfully used in the treatment of Philadelphia chromo- at the 2′-position of the purine ring. It is transported intracellularly
some negative myeloproliferative neoplasms, including myelofibrosis, by facilitated nucleoside diffusion and phosphorylated by the pyrimi-
polycythemia vera, and essential thrombocythema. Its leukemogenic dine salvage pathway enzyme deoxycytidine kinase. CdA is relatively
potential is uncertain, however, and it should be used with caution, resistant to deamination by CDD. CdA is readily converted to its
particularly in younger patients. Hydroxyurea has also been shown triphosphate derivative, 2′-chlorodeoxyadenosine-5′-triphosphate,
to reduce the incidence of painful crises in individuals with sickle cell particularly in cells of lymphoid origin, and is incorporated into
anemia in a subset of patients, a phenomenon that may result from tumor cell DNA by DNA polymerase-α. CdATP is also an effective
increases in red blood cell fetal hemoglobin levels. inhibitor of ribonucleotide reductase, which may contribute to lethal
effects. CdA induces cell death (apoptosis) in both cycling and
Fludarabine noncycling cells, possibly by promoting DNA fragmentation and by
depleting cells of ATP or NAD, or both.
Chemistry and Mechanism of Action: Fludarabine phosphate
is a fluorinated derivative of the nucleotide analog ara-A, which is Absorption, Fate, and Excretion: Relatively little pharmacoki-
resistant to deamination by the degradative enzyme CDD. It is netic information concerning CdA is available. The drug is most
converted intracellularly to its triphosphate derivative, which inhibits commonly administered as a 7-day continuous infusion or as a
ribonucleotide reductase, as well as DNA polymerase-α and DNA 2-hour infusion over 5 days. The bioavailability of CdA after subcu-
primase. Fluoro-ara-ATP is also incorporated into DNA, a process taneous (SC) administration approximates that of the IV route but
that appears to be essential for the induction of apoptosis in leukemic is less than that after oral administration. Renal excretion appears to
cells. Fludarabine is toxic to S-phase cells, but its ability to interfere be the major route of elimination. When given as a 2-hour infusion,
with DNA repair may contribute to lethality in their noncycling CdA has a relatively long terminal half-life (e.g., ≈6 hours), and
counterparts. plasma concentrations after such a schedule may approximate those
associated with the continuous infusion. Cerebrospinal fluid levels
Absorption, Fate, and Excretion: After IV injection, fludara- are approximately 25% of plasma concentrations.
bine phosphate is rapidly deaminated (i.e., within minutes) in the
plasma to its nucleoside derivative, 2′-fluoro-ara-A, which is then Preparation and Administration: For daily infusions, CdA is
converted intracellularly to its nucleotide form, 2′-fluoro-ara-AMP diluted under sterile conditions in bags containing 500 mL of 0.9%
by the pyrimidine salvage pathway enzyme, deoxycytidine kinase. sodium chloride injection, USP. The use of 5% dextrose solutions is
The half-life of 2′-fluoro-ara-A is approximately 10 hours; the not recommended because of enhanced degradation of the drug. For
primary mode of elimination is renal, with 25% of the total dose preparation of longer infusions (e.g., 7 days) the use of bacteriostatic
appearing in the urine as unchanged 2′-fluoro-ara-A. Total body sodium chloride injection, USP, is recommended. After being pre-
clearance of fludarabine is inversely correlated with serum pared, solutions of CdA should be refrigerated at a temperature
creatinine. between 4°C (40°F) and 8°C (47°F) for no more than 8 hours before
administration.
Preparation and Administration: Fludarabine is supplied as a
sterile powder in 50-mg vials containing 50 mg of mannitol and Toxic Effects: The major toxicity of CdA is myelosuppression,
sodium hydroxide to adjust the pH to 7.7. Material is reconstituted which is primarily observed after intermittent rather than continuous
in 2 mL of sterile water to yield a 25-mg/mL solution for injection. infusion. Other toxicities include fever, generally beginning several
The material may be stored at 4°C (40°F); because the reconstituted days after initiation of therapy, and increased susceptibility to oppor-
solution contains no antimicrobial preservative, the drug should be tunistic infections. Rare side effects include nausea and hepatic and
administered within 8 hours of formulation. renal toxicity.

Toxic Effects: The most common dose-limiting toxicity is myelo- Potential Drug Interactions: None reported.
suppression (neutropenia, thrombocytopenia, and anemia). Other
toxicities include fever, chills, infection, nausea, and vomiting. Rarer Therapeutic Indications in Hematology: CdA has shown
toxicities include malaise, fatigue, anorexia, and weakness. Patients significant activity in CLL and hairy cell leukemia. However, response
with CLL receiving fludarabine have experienced serious opportunis- rates in the former disorder appear to be somewhat less than those
tic infections and tumor lysis syndrome. The most serious toxicity of obtained with fludarabine; moreover, patients who have progressed
2
fludarabine when administered at high doses (>40 mg/m /day for 5 on fludarabine therapy infrequently respond to CdA. Other diseases
days) is irreversible neurotoxicity, including cortical blindness, nec- in which CdA has shown activity include NHL and Waldenström
rotizing leukoencephalopathy, and death. This phenomenon has macroglobulinemia.