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334 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 335

drug (IMiD), pomalidomide, is approved for patients refractory to hepatoma, and Kaposi sarcoma. It has established value in treating
lenalidomide and bortezomib. 163 myeloma refractory to first-line chemotherapy, as well as in newly diag-
The mechanism of action of thalidomide and analogues is incom- nosed patients. 172,173 In responding patients, all aspects of the disease,
pletely understood, as the compounds have a number of different including marrow infiltration with tumor cells, anemia, and perfor-
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actions, including a prominent antiangiogenic effect against tumors, mance status, improved with therapy. Thalidomide has synergistic mye-
immune modulation, and inhibition of cytokine secretion. They inhibit loma-inhibiting activity with glucocorticoids, interferon-α, bortezomib,
neovascularization in the mouse cornea, block proliferation of endo- and cytotoxic agents. However, lenalidomide, which has less-prominent
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thelial cells in culture, and inhibit secretions of vascular endothelial side effects and probably greater efficacy, has replaced thalidomide in
growth factor and other angiogenic cytokines. Thalidomide potently first-line regimens for myeloma. Pomalidomide is reserved for patients
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stimulates phosphorylation of the CD28 costimulatory molecule. refractory to lenalidomide and bortezomib, and retains impressive
This effect can lead to enhancement of T-cell function and activation activity in this setting.
of signaling pathways. Thalidomide has inhibitory effects on cytokine Thalidomide is generally well tolerated in oral doses of 50 to 1200
secretion, lowering levels of tumor necrosis factor-α and γ-interferon in mg daily, although higher doses are more challenging. In treating mye-
leprosy patients. In addition it enhances NK-cell numbers and function, loma, a 1-month trial is usually sufficient to observe a decline in para-
suppresses T-regulatory cells, and stimulates cytolytic T-cell function. protein and an improvement in symptoms, with doses typically used
It downregulates interferon regulatory factor 4 (IRF4), a myeloma sur- ranging from 50 to 200 mg/daily. Doses can be escalated up to 200 mg
vival factor. Although lenalidomide and pomalidomide have not been every 2 weeks until dose-limiting toxicity is reached at 600 to 800 mg/
studied as extensively as thalidomide preclinically, they have the same day, but these higher doses are rarely used. Patients older than age 65
spectrum of biologic actions but with greater potency. years are less tolerant of side effects, particularly sedation, constipation,
An additional IMiD site of action related to degradation of key fatigue, and peripheral sensory neuropathy, and receive a median dose
proteins has been identified. The IMiDs interact with cereblon, a protein of at most 400 mg/day, with lower doses (e.g., 100 mg/day) being prefer-
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that forms a complex with ubiquitin E3, and thereby promote the deg- able, whereas younger patients may tolerate up to a median of at most
radation of myc protein and other transcription factors. This effect on 800 mg/day, although again lower doses (e.g., 200 mg/day) are prefer-
E3 and cereblon binding partners has been implicated in the teratogenic able. With extended treatment at doses below 400 mg/day, the periph-
effects and antitumor activity of the IMiD compounds. 168 eral sensory neuropathy may become bothersome, but usually improves
with dose reduction or drug discontinuation. To avoid undue sedation,
Clinical Pharmacology of Thalidomide and Its Congeners the drug is given either in divided doses, morning and evening, or as
Thalidomide consists of two enantiomers that rapidly interconvert a single evening dose. Other side effects include rash, dizziness and
in solution and biologic fluids. Its two imide bonds are unstable and orthostatic hypotension, neutropenia, mood changes or depression,
undergo hydrolysis in solution. The poorly soluble drug undergoes slow and nausea. Hypersensitivity and bradycardia also have been reported.
and somewhat variable oral absorption with peak levels achieved in 2.9 Rarely patients may develop an interstitial pneumonitis or fulminant
to 4.3 hours 169,170 after oral doses ranging from 50 to 400 mg. There is no hepatic failure.
evidence for induction of metabolism on a daily dosing regimen. Drug Trials of thalidomide in combination with cytotoxic drugs or bio-
concentrations in plasma decay with a half-life of 5 to 7 hours, the major logics originally disclosed some unexpected toxicities. Thalidomide
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pathways for elimination including spontaneous hydrolysis of the imide in combination with doxorubicin or with prednisone is associated with
esters, and further CYP-mediated metabolism by the liver. At high doses an increased incidence of thromboembolism, a complication that can
of 1200 mg, the rate of clearance of drug from plasma decreases. Less than be prevented by concurrent treatment with low-molecular-weight hep-
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1 percent of the drug is excreted unchanged in the urine. No dose adjust- arin or aspirin. Because of its teratogenicity, patients of childbearing
ment is required for renal dysfunction, although its propensity for causing age should take precautions to prevent pregnancy while on therapy.
neuropathy may aggravate any underlying neuropathy secondary to prior In trials of thalidomide and interferon against renal cell carcinoma, in
exposures, renal failure or amyloidosis, making dose reduction prudent, which high doses of interferon (9 million IU subcutaneously three times
especially when used in combination with other agents. per week) were used, four of 13 patients developed complex partial sei-
Lenalidomide is well absorbed orally in doses up to 400 mg, and zures and visual disturbances. Two of 19 patients on thalidomide with
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usually given in doses up to 25 mg daily; it exhibits a plasma half-life low-dose interferon (1.5 to 3 million IU three times weekly) developed
of 3 hours. Approximately 70 percent of administered drug is excreted complex partial seizures in a trial against melanoma.
unchanged by the renal route, the remainder appearing in the feces In the United States, thalidomide and its analogues are approved
unchanged. Dose adjustments are therefore recommended for patients for use under a special risk evaluation and mitigation strategy (REMS),
in moderate (10 mg/day for CrCl of 30 to 50 mL/min) or severe (10 mg with restricted pharmacy access and a special consent form, to assure
every other day for CrCl <30 mL/min) renal failure. For those on dial- that pregnant women are not given these agents.
ysis, the recommended dose is 5 mg once daily, with the same day dose The analogue, lenalidomide, with significant activity against mye-
given following dialysis. loma, causes much less sedation, constipation, and neurotoxicity, but
Pomalidomide is given orally in doses of up to 4 mg per day. It has prominent myelosuppression in 20 percent of patients. It is proving to
a long plasma half-life of 7.5 hours in myeloma patients, and is elimi- be highly effective in remission induction with bortezomib and predni-
nated by CYP1A2 and CYP3A4 hydroxylation in the liver with minimal sone or with prednisone alone. Used in oral doses of up to 25 mg/day
renal clearance. Inducers or inhibitors of CYP3A4 metabolism (prom- for 21 of 28 days, it is dramatically effective in normalizing hematologic
inently antibiotics and HIV drugs) and inhibitors of the MDR1 efflux parameters in the subset of patients with myelodysplasia who have a
transporter (natural products and targeted cancer therapies) should be 5q– deletion on cytogenetics. A gene expression profile characteristic
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used in combination with pomalidomide with caution. 171 of lenalidomide responders has been reported. Lenalidomide pro-
duces dramatic tumor swelling (tumor flare reaction) and tumor lysis in
Clinical Use patients with CLL, a potentially fatal complication, even in patients with
Thalidomide has been evaluated against a number of human malig- disease refractory to conventional agents. In CLL, it is equally effective
nancies, with occasional responses in brain tumors, renal cell cancer, in patients with poor prognostic cytogenetics (chromosomes 11 and

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