Page 1029 - Hematology_ Basic Principles and Practice ( PDFDrive )

912 Part VII Hematologic Malignancies

Therapeutic Indications in Hematology: Imatinib is consid- may be seen if a topoisomerase I inhibitor (topotecan) is given after
ered first-line therapy in Ph+ CML and has activity in accelerated or an alkylating agent, suggesting that topoisomerase I may be involved
blast-phase CML. Some effect has been shown in ALL as well as in the repair of alkylator-induced DNA damage.
hypereosinophilic syndrome and polycythemia vera.
Therapeutic Indications in Hematology: Topotecan has activ-
Topotecan (Hycamtin) ity in MDS, AML, chronic myeloid leukemia, and MM.
Chemistry and Mechanism of Action: Topotecan is a semisyn- Vorinostat (Zolinza)
thetic derivative of camptothecin that stabilizes a complex between
DNA topoisomerase I and DNA. The cytotoxic effect of this drug is Chemistry and Mechanism of Action: Vorinostat is a HDAC
believed to result from the collision of DNA replication forks with a inhibitor. It inhibits HDAC 1, HDAC2, HDAC3, and HDAC6 at
ternary complex of topoisomerase I, DNA, and topotecan. The nanomolar concentrations. Inhibition prevents removal of the acetyl
resulting double-strand DNA breaks are lethal. The lactone form of groups from lysine residues in target histones and transcription
topotecan, which predominates at an acidic pH, is a much more factors. Loss of deacetylase function results in persistence of acetyl
potent inhibitor of DNA topoisomerase I. groups on histones, resulting in larger segments of open chromatin
and a general increase in gene expression. Often this promotes dif-
Absorption, Fate, and Excretion: At neutral or physiologic pH, ferentiation and cell cycle arrest with apoptosis. The number of genes
the carboxylate form of topotecan is favored, and at a pH less than affected continues to grow so that the impact of vorinostat is complex.
7, the lactone form is favored. Topotecan has been given as a bolus
or by continuous infusion. In less than 1 hour after infusion, most Absorption, Fate, and Excretion: Reported pharmacokinetics
of the circulating drug in the plasma is in the carboxylate form after a 400-mg oral administration are an AUC of 5.5 micromolar-
because of the physiologic pH. The terminal half-life of the lactone hours, a C max of 1.2 micromolar, and T max of 2–10 hours. Fatty meals
form of this S-phase–specific agent is 2.6 hours, and the terminal decrease the rate of absorption but increase overall drug levels. There
half-life of the total drug is 3.3 hours. Thirty six percent of an IV is no recommended dosing relative to meals. Vorinostat is heavily
dose is excreted unchanged in the urine, and there is a 1.5-fold plasma protein absorbed. It undergoes glucuronidation hydrolysis,
concentration of the drug in bile. Cerebrospinal fluid levels of topo- and later β-oxidation to inactive metabolites. Little is excreted
tecan lactone reach approximately 32% of plasma levels. Dose unchanged.
adjustment is required for a creatinine clearance less than 60 mL/
min, but no adjustment is necessary for a bilirubin up to 10 mg/dL. Preparation and Administration: Oral dosing of 400 mg with
food is standard. If side effects are noted, reduce the dose to 300 mg.
Preparation and Administration: Topotecan is commercially There is no approved pediatric dosing.
available as 4-mg vials that are reconstituted with 4 mL of sterile
water. This solution can be further diluted in normal saline or 5% Toxic Effects: Many side effects are noted. Common are fatigue,
dextrose in water and should be used immediately. thrombocytopenia, muscle spasms, and anorexia. Serious reported
adverse effects in clinical trials included pulmonary embolism in
Toxic Effects: The dose-limiting toxicity for topotecan for all 4.7% and anemia in 2.3%.
schedules is neutropenia. Thrombocytopenia and anemia are less
common, although there is an increase in thrombocytopenia with Potential Drug Interactions: Vorinostat can prolong the effect
continuous infusion schedules. Other less common and mild toxici- of coumadin, raising the international normalized ratio. It can also
ties include nausea, vomiting, diarrhea, fever, fatigue, alopecia, skin induce glucose intolerance.
rash, and increased liver function test results. Mucositis has been seen
with prolonged infusion schedules over 5 days or when topotecan is Therapeutic Indications in Hematology: Vorinostat is
given in higher doses. approved for cutaneous manifestations of CTCL in patients who have
become refractory to standard treatments. It is being tested in other
Potential Drug Interactions: In vitro data suggest that there may disorders such as myeloma and leukemias to determine whether it
be some synergism if a topoisomerase I inhibitor is given before a works through the HDACs or through altered expression of numer-
topoisomerase II inhibitor. In vitro data also suggest that synergism ous proteins.