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336 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 337

Torsade de pointes occurs infrequently during arsenic trioxide myelomonocytic leukemia. The decitabine dose resulting in optimal
treatment, but requires immediate treatment with intravenous magne- hypomethylation is 20 mg/m intravenously daily for 5 days every 4
2
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sium sulfate, potassium repletion, and defibrillation if the arrhythmia weeks, although alternative schedules employing lower doses have
and hemodynamic instability persist. 197 been used. Dose adjustment and delays in repeat cycles may become
A maximum plasma concentration of 5.5 to 7.3 μM was achieved necessary because of myelosuppression.
in the initial studies from China, and small amounts of drug and the The primary clinical toxicities of both drugs include reversible mye-
methylated metabolite are eliminated in the urine, the rest remaining losuppression, nausea and vomiting with higher doses, hepatic dysfunc-
in tissues. 198 tion, myalgias, fever, and rash. Both compounds are rapidly deaminated
and converted to a chemically unstable azauridine or aza-deoxyuridine
metabolite that immediately degrades into inactive products. 202
EPIGENETIC AGENTS A significant portion of patients with MDS does not respond to
demethylating agents, and all will ultimately relapse. Azacitidine is ini-
DEMETHYLATING AGENTS tially phosphorylated by a different kinase (uridine-cytidine kinase) and
DNA methyltransferases (DNMTs) regulate transcription by meth- so may benefit patients unresponsive to azacytidine. 205
ylating CpG promoter regions of DNA and thereby silencing gene Clinical trials of azacytosine nucleosides with histone deacetylase
expression. Mutations associated with AML, including isocitrate dehy- (HDAC) inhibitors have demonstrated promising results in phase I tri-
drogenase 1 and 2 (IDH1 and IDH2) mutations, TET2, and mutations als in MDS and AML. 205,207 Second-generation hypomethylating agents
that activate DNMT, result in increased DNA methylation. Hyper- are currently in clinical trials and hold the promise of more convenient
methylation blocks differentiation and drives cellular proliferation. dosing schedules and improved toxicity profiles. 205
Two DNA demethylating agents, azacitidine and decitabine, have been
approved for treatment of MDS. Both drugs become incorporated into
DNA, substituting for cytosine bases, and form a suicide covalent bond HISTONE DEACETYLASE INHIBITORS
with DNMT. The two drugs differ in their activation pathways and in Histone acetylation is an important determinant of gene expression and
their effects on nucleic acid methylation. Decitabine is phosphorylated is regulated by the addition and removal of acetyl groups from lysine
by dCK whereas azacitidine is activated by cytidine kinase. Decitabine amino acid residues on histones. The removal of acetyl groups facilitates
nucleotide is incorporated only into DNA, while azacitidine is found chromatin compaction thereby decreasing gene expression and is medi-
in both RNA and DNA. The clinical response to these drugs has not ated by HDACs. The four classes of HDACs are differentially expressed.
been correlated with either global changes in DNA methylation or with HDACs 1 to 3 are overexpressed in many cancer types. Overexpression
methylation of specific genes. Indeed, while traditional thinking has of these HDACs is associated with repression of tumor suppressor and
taught that DNA methylation invariably leads to gene silencing, newer DNA repair genes, and confers a poor prognosis. 208,209 HDAC inhibitors
studies have demonstrated that many actively transcribed genes have reverse these changes. They maintain chromatin acetylation and decom-
high levels of DNA methylation and that the tissue context and specific paction and promote expression of tumor-suppressor genes, thereby
patterns of methylated DNA may play an important role in determining inducing terminal differentiation and apoptosis of tumor cells. Inter-
transcriptional activity. 199 estingly, HDACs may paradoxically play a role as tumor suppressors as
Azacitidine received FDA approval for therapy of MDS on the well, as knockout models in mice exhibit spontaneous tumorigenesis
basis of reported improvement in Hgb, white cells, or platelets, delayed through a p53-mediated mechanism. 208,210,211 HDACs deacetylate multi-
progression to AML, improved quality of life, and improved overall sur- ple nonhistone proteins, including p53 and members of the DNA repair
vival. In a more recent four-arm phase III trial in higher-risk MDS complex, but these actions have uncertain significance.
200
patients, azacitidine was compared with best supportive care, low-dose Three HDAC inhibitors are approved for clinical use: vorinostat
ara-C, or induction chemotherapy with anthracycline and ara-C. The and romidepsin. Vorinostat is a hydroxamic acid derivative, whereas
median overall survival was 24.5 months in the azacitidine arm com- romidepsin is a natural product produced by Chromobacterium vio-
pared with 15 months for the other arms. 201 laceum. Both HDAC inhibitors block the zinc-dependent enzymatic
Decitabine was approved on the basis of a 30 percent overall hema- activity of these HDACs and work predominantly against class 1
tologic response rate in MDS patients. For those with intermediate- HDACs (HDACs 1 to 3). In lymphoma cells, romidepsin was able to
202
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or high-risk disease, time to AML or death was significantly delayed, overcome the prosurvival effects of BCL-2 whereas vorinostat was not.
but there is no improvement as yet in overall survival with this drug. HDAC inhibitors are active in cutaneous T-cell lymphoma. Pabi-
203
While the two agents have not been compared head to head in MDS, a nostat was recently approved, in combination with bortezomib and dex-
meta-analysis showed a significant overall survival benefit versus sup- amethasone, for relapsed multiple myeloma. Romidepsin is useful against
portive care only for azacitidine. A retrospective review found no peripheral T-cell lymphoma. FDA approval of vorinostat was based upon
204
significant difference in efficacy between the two compounds except in an overall partial response rate of 30 percent and a median response dura-
patients older than 65 years of age, for whom azacitidine resulted in tion of 168 days in patients with cutaneous T-cell lymphoma who had
improved survival and a more favorable toxicity profile. progressed on at least two prior regimens. Romidepsin was approved
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Both agents increase HgbF levels in sickle cell anemia and thalas- for use in cutaneous T-cell lymphoma as well after clinical trials demon-
semia, and reduce symptomatic episodes, but have been superseded by strated an overall response rate of 34 percent, including 7 percent com-
hydroxyurea for this indication. plete responses in previously treated patients. 214
Azacitidine is approved for parenteral or subcutaneous adminis- Romidepsin is approved for use in patients with who have received
tration at 75 mg/m /day for 7 days every 28 days, a regimen that has at least one prior therapy. In these patients it achieved objective
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been shown to result in maximal DNA hypomethylation. A daily- response rates of up to 38 percent. The median progression free survival
times-five regimen appears to have similar efficacy. The median num- for the 15 percent of patients in complete remission was 29 months. 215,216
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ber of cycles needed for response is three, but 80 percent of responses Vorinostat is administered orally at 400 mg/day. It is predominantly
occurred before the sixth cycle. An oral formulation is currently cleared by glucuronidation and side change oxidation by cytochrome
206
being developed and has demonstrated activity in MDS and chronic metabolism, and should be dose reduced to 300 mg/day for mild and

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