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324 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 325

mediated by guanase and xanthine oxidase, contributes to clearance. B and T lymphocytes, lowering CD4 T-cell counts to 150 to 200 cells/μL
Dose reduction is not necessary when 6-TG and allopurinol are admin- and predisposing patients to opportunistic infections. In patients with a
istered together. large tumor burden, rapid tumor lysis may rarely lead to hyperuricemia,
renal failure, and hypocalcemia (tumor lysis syndrome). Thus, patients
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Adverse Effects of 6-Thiopurines should be well hydrated and their urine alkalinized prior to beginning
Both 6-TG and 6-MP are myelotoxic, producing nadirs of white blood therapy. The primary acute toxicity is reversible myelosuppression.
59
cells and platelets at 7 to 10 days after treatment. Moderate nausea Peripheral sensory and motor neuropathy may occur during standard-
and vomiting may also be observed. Patients may experience mild but dose therapy; autoimmune phenomena, including prolonged hypothy-
rapidly reversible hepatotoxicity after treatment with either compound. roidism, neutropenia and hemolytic anemia with both warm and cold
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Cirrhosis has occurred in some children with leukemia who are receiv- antibodies, have been reported. Approximately 10 percent of CLL
ing long-term therapy with 6-MP. TPMT, which inactivates 6-thiopu- patients receiving fludarabine may develop a hypersensitivity syndrome
rines, occurs in several polymorphic forms that fail to metabolize the of pulmonary infiltrates, hypoxemia, and fever, responsive to glucocor-
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analogues. Approximately one person in 10 of the white population is ticoids. Myelodysplasia and acute leukemias, with chromosome 7p
heterozygous for ineffective polymorphic forms of the enzyme and will deletions, have been reported as infrequent late complications. 70
have significantly greater myelosuppression, whereas one patient in 300
is homozygous for the inactive forms, accumulates high concentrations CLADRIBINE (2-CHLORODEOXYADENOSINE,
of thioguanine nucleotides in both tumor and normal cells, and is at risk
for overwhelming toxicity, even with greatly reduced doses of 6-MP. 60 2-CDA)
Other toxicities may include hypersensitivity reactions (fever, The extreme sensitivity of normal and malignant lymphocytes to deam-
rash), interstitial pneumonitis; pancreatitis; opportunistic infection, ination-resistant purine analogues is further exemplified by the potent
and an increased incidence of AML in patients receiving chronic immu- activity of cladribine in hairy cell leukemia, CLL, and low-grade lym-
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nosuppressive treatment with 6-MP. phomas. A single course of cladribine, typically 0.09 mg/kg per day for
7 days by continuous intravenous infusion, induces complete response in
80 percent of patients with hairy cell leukemia. Administration by sub-
FLUDARABINE PHOSPHATE cutaneous injection or by 2-hour intravenous infusion daily for 5 days to
Originally synthesized as a deamination-resistant analogue of ade- the same total dose achieves similar results. The drug has much the same
nosine, fludarabine phosphate contains two important substitutions: a intracellular fate as fludarabine, undergoing phosphorylation by dCK
fluorine attached to the purine ring, which renders the drug resistant and further conversion to a triphosphate that becomes incorporated into
to deamination, and an arabinose sugar in place of deoxyribose, which DNA. The triphosphate of cladribine has a long intracellular half-life
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leads to its pharmacologic activity as an inhibitor of DNA synthesis of 9.7 hours in CLL cells isolated from patients treated with the drug.
and ribonucleotide reductase. It has outstanding activity in CLL. It is The triphosphate has multiple metabolic effects, disrupting oxidative
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strongly immunosuppressive, like the other purine analogues, and is phosphorylation in mitochondria, inhibiting RNR and depleting nico-
frequently used for this purpose in nonmyeloablative allogeneic mar- tinamide adenine dinucleotide levels in tumor cells. All of these actions
row transplantation and in the treatment of autoimmune diseases. may explain the drug’s toxicity to slowly dividing lymphoid malignancies
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Activation of fludarabine phosphate requires removal of the phos- such as hairy cell leukemia and CLL. The actual mechanisms by which
phate group in plasma to allow cellular uptake by nucleoside transport- cladribine induces DNA strand breaks are not completely understood.
ers, and then intracellular rephosphorylation. Fludarabine is activated However, similar to fludarabine, it inhibits DNA chain extension and
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to the monophosphate level by dCK. The triphosphate inhibits DNA daughter strand synthesis. Furthermore, the drug’s inhibition of RNR
polymerase and becomes incorporated into both DNA and RNA. Its lowers levels of the competitive dATP. The cumulative effects of cladrib-
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mechanism of cytotoxicity results from DNA chain termination and ine induce apoptosis (programmed cell death).
induction of apoptosis, although it also inhibits ribonucleotide reduc- Cladribine is eliminated primarily (>50 percent) by renal excre-
tase (RNR), a self-potentiating activity that decreases intracellular tion, with a terminal plasma half-life of 7 hours. In a patient with renal
deoxyadenosine triphosphate (dATP) and increases fludarabine incor- failure, continuous flow hemodialysis effectively cleared the drug and
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poration into DNA. Its triphosphate has a long intracellular half-life of prevented serious myelosuppression. Cladribine retains effectiveness
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15 hours in CLL cells. Resistance has been ascribed to decreased active in at least a fraction of hairy cell leukemia patients resistant to deoxy-
uptake, a deficiency of dCK, increased efflux, or increased RNR. coformycin or fludarabine, although clinical experience with sequential
The drug is available in the United States as an intravenous prepa- use of these drugs is limited. Toxicities of cladribine include tran-
ration, and for oral use. It has 60 to 80 percent bioavailability. Because it sient myelosuppression, fever, tumor lysis syndrome, and occasional
is resistant to adenosine deaminase, fludarabine is eliminated primarily opportunistic infections possibly related to immunosuppression. The
by renal excretion (60 percent), with a terminal half-life of 10 hours. development of cumulative thrombocytopenia during treatment with
For patients treated with fludarabine, the standard intravenous dose is repeated courses of the drug may limit its use. Resistance develops in
25 mg/m daily for 5 days, whereas the approved oral dose is 40 mg/m experimental tumors through decreased uptake, loss of the activating
2
2
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daily for 5 days. In patients with renal impairment, a 20 percent dose enzyme dCK, increased RNR activity, increased efflux, or by induction
reduction for a CrCl of 17 to 40 mL/min/m , and a 40 percent dose of 5′-nucleotidase activity.
2
reduction for a CrCl less than 17 mL/min/m yields an area under the
2
curve approximately equal to that seen in patients with normal renal CLOFARABINE
function receiving full doses of fludarabine. 65,66
When administered at these doses, fludarabine causes only moder- (2-CHLORO-2′-FLUORO-ARABINOSYLADENINE)
ate myelosuppression. In CLL patients, its antileukemic effect will lead This analogue has halogen substitutions on both the purine ring and
to a progressive improvement in marrow function over a period of two arabinose sugar, resulting in a ready uptake and activation, to a highly
to three cycles of treatment, with a median time to disease progression of stable intracellular triphosphate (half-life of 24 hours), which termi-
31 months. However, the drug also exerts cytotoxic effects against both nates DNA synthesis, inhibits RNR, and induces apoptosis. The usual

Kaushansky_chapter 22_p0313-0352.indd 324 9/18/15 10:24 PM