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

17 deletions). It must be started in low doses (beginning at 2.5 to 5 mg/ to ATRA therapy. Induction of CYP26A1-mediated metabolism is
day and escalating thereafter) to avoid tumor flare reaction and renal suspected to underlie this accelerated clearance, and may account for
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failure. It has rarely been associated with severe hepatic and renal the high rate of disease recurrence if ATRA is used as a single agent.
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toxicity. The primary toxicities of ATRA resemble those of other retinoids and
Like thalidomide, lenalidomide in combination with anthracy- vitamin A, specifically dry skin, cheilitis, mild and reversible hepatic
clines or glucocorticoids causes a 15 percent incidence of thrombotic dysfunction, bone tenderness and hyperostosis on radiography, hyper-
events, and in these combinations should be administered with low-mo- calcemia, hyperlipidemia, and occasional cases of pseudotumor cerebri.
lecular-weight heparin, although prospective trials of anticoagulation Imidazole antifungals block the degradation of ATRA and may lead to
are lacking. 180 hypercalcemia and renal failure. In addition, approximately 15 percent
Pomalidomide’s prominent toxicity is neutropenia in 50 to 60 per- of patients with APL, particularly those with an initial leukemic cell
cent of patients, and thrombocytopenia in 25 percent. It has little sedat- count greater than 5000/μL, develop a syndrome of hyperleukocytosis,
ing effects and causes neuropathy in 10 percent or fewer subjects. It is fever, altered mental status, pleural and pericardial effusions, and respi-
highly active in relapsed, refractory myeloma and particularly in com- ratory failure (the “retinoic acid syndrome”). Hyperleukocytosis and
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bination with various agents, including dexamethasone and proteasome leukocyte adherence to small vessels results from a rapid increase in the
inhibitors, such as bortezomib and carfilzomib. Rare toxicities include number of mature leukemic cells in the blood and from the increased
thromboembolism (3 percent) and isolated cases of hepatic failure. 163 expression of integrins on the leukemic cell surface and secretion of
cytokines in response to ATRA. In patients with white blood cell counts
3
above 20 × 10 cells/μL, pleural and pericardial effusions and periph-
DIFFERENTIATING AGENTS eral edema develop rapidly, and respiratory distress, cardiac failure, and
renal insufficiency may lead to death. Anecdotal reports indicate that
Certain chemical agents have the ability to cause terminal differentia- high-dose glucocorticoids reverse this syndrome, which is mediated
tion (maturation) of malignant cells. 181,182 The most prominent among by leukocyte adhesion and clogging of small vessels and/or by cytok-
these are members of the vitamin A family (carotenes and retinoids), ine release. The early introduction of cytotoxic chemotherapy during
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vitamin D and its analogues, phenylacetic acid, various cytotoxic agents remission induction, and the use of dexamethasone sodium phosphate
used in low concentrations (such as hydroxyurea), inhibitors of DNA (10 mg twice daily for 3 or more days in patients with initial leukemic
methylation such as 5-azacytidine and 5-aza-2′-deoxycytidine or decit- counts of greater than 5000 cells/μL), drastically lower the incidence of
abine, and inhibitors of histone deacetylase, exemplified by vorinostat, the syndrome and improve the safety of ATRA therapy.
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depsipeptide, and various benzamides. In addition, biologic agents
such as the interferons and interleukins induce terminal differentiation
of both malignant and normal cells, but the role of terminal differenti- ARSENIC TRIOXIDE
ation in the anticancer action of these drugs in humans is uncertain, as
they have multiple biologic effects. In the 1930s, arsenic was used to treat CML and other malignancies with
little effect. Based on further clinical trials of arsenic trioxide (As O ) in
2
3
Harbin, China, in 1992, it resurfaced as an impressively effective treat-
RETINOIDS ment for relapsed APL, and appears to also be active against myeloma
As the first effective terminal differentiating agent in cancer therapy, and myelodysplasia. Its mechanism of action probably stems from its
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ATRA induces complete responses in a high percentage of patients with ability to promote free radical production. It inhibits the detoxification
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APL, and has become a standard member of the combination regimen of free radicals and inactivates glutathione, an important radical scaven-
for treatment and cure of this disease. ATRA acts through binding ger. It promotes degradation of the PML-RARα fusion protein, and
184
194
195
to a nuclear receptor formed by the heterodimerization of the retin- upregulates p53 and proapoptotic proteins. The cumulative effect is to
oic acid receptor-α (RARα) and its partner, the retinoid X receptor. In induce maturation and promote apoptosis in APL cells. In addition, it
APL, an abnormal fusion protein, composed of portions of the RARα has antiangiogenic effects. The sum of these actions is potent antitumor
and a unique transcription factor (the PML gene product), results from activity in some but not all tumor cells. In APL patients refractory to
the characteristic 15;17 chromosomal translocation found in this dis- ATRA and conventional chemotherapy, it produces strikingly durable
ease. The fusion protein has a lower affinity for retinoids than does complete responses, and is therefore under study as a part of primary
185
the wild-type molecule. High concentrations of retinoids are required treatment regimens for this disease.
to displace a corepressor bound to the protein, and activate key differen- Patients are treated with a 2-hour intravenous infusion of
tiation factors such as CCAAT/enhancer binding protein (C/EBP) and 0.15 mg/kg day for up to 60 days, or until marrow remission is achieved,
PU.1. The fusion protein forms a variety of homo- and heterodimers with further consolidation therapy beginning 3 weeks after remission.
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that regulate genes and increase leukemic stem cell renewal, and sup- Remissions appear in 2 to 3 months with evidence of leukemic cell dif-
press apoptosis and DNA repair, further contributing to progression of ferentiation and a progressive blood leukocytosis after 2 weeks of ther-
leukemia. In experimental settings, resistance to ATRA differentiating apy. Side effects of arsenic trioxide in APL may include hyperglycemia,
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activity results from mutation or loss of retinoid binding in the PML- elevated liver enzymes, and hypokalemia, none of which require discon-
RARα fusion gene, indicating that the fusion gene product plays a role tinuation of therapy. Occasional patients complain of fatigue, dysesthe-
in retinoid responsiveness, and sensitivity can be restored by transfec- sias, and lightheadedness. A pulmonary distress syndrome, similar to
tion of a functional RARα gene. 187 that encountered with APL cell maturation after ATRA therapy, occurs
ATRA is administered to APL patients in oral doses of 25 to 45 mg/ in approximately 10 percent of patients, and is managed with glucocor-
m per day until complete remission is achieved and reaches peak serum ticoids, oxygen, and temporary withholding of arsenic trioxide. Arsenic
2
levels of 300 ng/mL 1 to 2 hours after administration. It is also used in trioxide prolongs the cardiac QT interval, and uncommonly produces
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remission maintenance, with 6-MP, methotrexate, or ara-C. The parent atrial or ventricular arrhythmias; it is important to maintain serum
drug disappears from serum with a half-life of less than 1 hour during potassium at normal concentrations during arsenic trioxide therapy,
the initial course of treatment, but its rate of clearance greatly acceler- and to avoid use of other drugs that prolong the QT interval, such as
ates with continued treatment, a factor that may contribute to resistance macrolide antibiotics, methadone, or quinidine.

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