DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1704 Cladribine is considered the drug of choice in
hairy cell leukemia. Eighty percent of patients achieve
a complete response after a single course of therapy.
The drug also is active in CLL; low-grade lymphomas;
Langerhans cell histiocytosis; CTCLs, including mycosis
fungoides and the Sézary syndrome; and
Waldenström macroglobulinemia.
Clinical Toxicities. The major dose-limiting toxicity of
cladribine is myelosuppression. Cumulative thrombocytopenia
may occur with repeated courses.
Opportunistic infections are common and correlate with
decreased CD4 + cell counts. Other toxic effects include
nausea, infections, high fever, headache, fatigue, skin
rashes, and tumor lysis syndrome.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Clofarabine (2-Chloro-2′-Fluoro-
Arabinosyladenine)
This analog resulted from incorporating the 2-chloro,
glycosylase-resistant substituent of cladribine and a
2′-fluoro-arabinosyl substitution, which further
strengthens stability and enhances uptake and phosphorylation.
The resulting compound is approved for pediatric
ALL after failure of two prior therapies.
For these patients, it produces complete remissions in 20-30 % of
patients. It has activity as well in pediatric and adult AML and in
myelodysplasia. Its uptake and metabolic activation in tumor cells follow
the same path as cladribine and the other purine nucleosides, although it
is more readily phosphorylated by dCK. It incorporates into DNA, where
it terminates DNA synthesis and leads to apoptosis.
Absorption, Fate, and Distribution. Clofarabine triphosphate has a
long intracellular t 1/2
of 24 hours. Its antitumor activity is ascribed to
its incorporation into DNA, resulting in chain termination. Like fludarabine,
clofarabine inhibits RNR (Bonate et al., 2006). In children,
following administration of usual doses of 52 mg/m 2 given as a 2-hour
infusion daily for 5 days, clofarabine has a primary elimination t 1/2
in
plasma of 6.5 hours, and the majority of drug is excreted unchanged
in the urine. Doses should be adjusted according to reductions in CrCl,
although precise guidelines are not available.
Clinical Toxicities. The primary toxicities are myelosuppression; a
clinical syndrome of hypotension, tachyphemia, pulmonary edema,
organ dysfunction, and fever, all suggestive of capillary leak syndrome
and cytokine release; elevated hepatic enzymes and increased
bilirubin; nausea, vomiting, and diarrhea; and hypokalemia and
hypophosphatemia. Evidence of capillary leak should lead to immediate
discontinuation of the drug.
Nelarabine (6-Methoxy-
Arabinosyl-Guanine)
The only guanine nucleoside in clinical use, this agent
has selective activity against acute T-cell leukemia
(20% complete responses) and the closely related T-cell
lymphoblastic lymphoma and is approved for use in
relapsed/refractory patients. Its basic mechanism of
action closely resembles that of the other purine nucleosides,
in that it is incorporated into DNA and terminates
DNA synthesis. It has selective toxicity for T
lymphocytes and T-cell malignancies.
H 2 N
N
HOCH 2
HO
NELARABINE
OH
Absorption, Fate, and Distribution. Following infusion, the parent
methoxy compound is rapidly activated in blood and tissues by
adenosine deaminase–mediated cleavage of the methyl group, yielding
the phosphorylase resistant Ara-G, which has a longer plasma
t 1/2
of 3 hours. The active metabolite is transported into tumor cells,
where it is activated by CdK to the monophosphate and thence to a
triphosphate. Ara-G triphosphate (Ara-GTP) is incorporated into
DNA and terminates DNA synthesis (Sanford and Lyseng-
Williamson, 2008). The drug and its metabolite, Ara-G, are primarily
eliminated by metabolism to guanine, and a smaller fraction is
eliminated by renal excretion of Ara-G. The dose should not be
adjusted for mild to moderate (CrCl >50 mg/mL) renal dysfunction
(Sanford and Lyseng-Williamson, 2008), but the drug should be used
with close clinical monitoring in patients with more severe renal
impairment. Adults are given a dose of 1500 mg/m 2 intravenously as
a 2-hour infusion on days 1, 3, and 5 of a 21-day cycle, and children
are given a lower dose of 650 mg/m 2 /day intravenously for 5 days
and repeated every 21 days.
Clinical Toxicities. Side effects include myelosuppression and liver
function test abnormalities, as well as frequent, serious neurological
sequelae, such as seizures, delirium, somnolence, peripheral neuropathy,
or Guillain-Barré syndrome. Neurological side effects may
not be reversible.
Pentostatin (2′-Deoxycoformycin)
O
N
CH 3
Pentostatin (2′-deoxycoformycin; see Figure 61–11), a transitionstate
analog of the intermediate in the adenosine deaminase (ADA)
reaction, potently inhibits ADA. Its effects mimic the phenotype of
genetic ADA deficiency (severe immunodeficiency affecting both T-
and B-cell functions). It was isolated from fermentation cultures of
Streptomyces antibioticus. Inhibition of ADA by pentostatin leads
to accumulation of intracellular adenosine and deoxyadenosine
nucleotides, which can block DNA synthesis by inhibiting RNR.
O
N
N