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

moderate hepatic impairment. It is contraindicated in patients with Certain cancers, including subsets of AML, gliomas, intrahe-
severe hepatic impairment. It has a plasma half-life of 2 hours, although patic cholangiosarcomas, breast and lung cancers, and central chon-
217
histones remain hyperacetylated for many hours. Renal elimination does drosarcomas harbor IDH1/2 mutations that confer a gain of function.
218
not play a major role in the drug’s clearance. Romidepsin is admin- These mutated enzymes (commonly mutated at arginine 132 of IDH1
2
istered as a 4-hour intravenous infusion of 14 mg/m on days 1, 8, and or arginine 170 of IDH2) convert αKG to the oncometabolite (R)-2-
2
15 of a 28-day treatment cycle. A dose reduction to 10 mg/m is possi- hydroxyglutarate (2HG). High concentrations of 2HG inhibit histone
ble in patients who experience high-grade toxicities. Romidepsin is and DNA demethylation by competing with the dioxygenase function
219
metabolized primarily by CYP3A4 and by glucuronidation, and is rapidly of the TET family of enzymes and Jumonji-C domain (JMJC) family of
cleared with a short half-life of approximately 3.5 hours. Asian patients histone lysine demethylases. The result of IDH mutations is hypermeth-
220
with the 2B57 genotype of uridine diphosphate (UDP)-glucuronyl trans- ylation of both DNA and histones and a block in differentiation. IDH1
ferase may experience delayed clearance and increased toxicity. or IDH2 mutations are present in 25 percent of AML where they confer
Both HDACs are generally well tolerated. The most common adverse a favorable prognosis. At the same time, IDH mutations in MDS and
events for vorinostat are diarrhea, fatigue, nausea, and anorexia, and lab- other myeloproliferative neoplasms may place patients at an increased
oratory abnormalities including, hyperglycemia, thrombocytopenia, and risk for transformation to AML. High levels of 2HG are measurable
221
proteinuria. For romidepsin, nausea, vomiting, infection, fatigue, and in plasma and urine in patients with IDH mutations, and may serve as a
213
212
myelosuppression were the primary toxicities. Significant QTc prolon- sensitive measure of treatment response and may reflect the presence of
222
gation and T-wave flattening but the electrocardiogram (ECG) changes minimal residual disease. 2HG in IDH mutant solid tumors may also
were not associated with clinical cardiotoxicity. Still, it is important to be imaged by magnetic resonance imaging (MRI) spectroscopy.
ensure electrolyte levels are normalized prior to and throughout therapy. Small molecule inhibitors of IDH mutant enzymes have been
Multiple newer HDACs have been extensively tested in clinical identified. One such inhibitor binds at the dimer interface in an allosteric
trials, although none has proven superior to vorinostat or romidepsin. fashion and exhibits uncompetitive inhibition of mutant IDH2, with
One new agent, panobinostat, has demonstrated promising results in great specificity for mutant IDH2 as compared to the wild-type enzyme.
phase II trials against cutaneous T-cell lymphoma, Hodgkin lymphoma, Mutant AML cells cultured ex vivo in the presence of these inhibitors
and Waldenström macroglobulinemia. 208 undergo differentiation. 220
An oral formulation of the mutant IDH2 inhibitor has shown
FUTURE EPIGENETIC TARGETS promising remission-inducing activity in its initial clinical trial. 220A
Isocitrate Dehydrogenase 2 Inhibitors
Isocitrate dehydrogenase (IDH) is a metabolic enzyme that converts DOT1L Inhibitors
isocitrate to α-ketoglutarate (αKG) (Fig. 22–6), a cofactor in dioxyge- Histone methylation also plays a role in transcriptional regulation.
nase reaction that precedes demethylation of histones and the DNA. Histone methylation leads to exposure of DNA promoter sites, with
effects on gene expression. DOT1L, a histone methyltransferase,
catalyzes the hypermethylation of specific lysine residues on histone
H3 (H3K79), and thereby regulates RNA polymerase II–mediated tran-
Citrate
scriptional elongation. In leukemias characterized by translocations
involving the MLL gene, fusion proteins are created that recruit DOT1L
Isocitrate
to transcription factor (HOXA9 and MEIS1) promoter sites, resulting
IDH in leukemogenesis. MLL translocations are seen in 5 to 10 percent of
acute leukemias of lymphoid, myeloid, or mixed/indeterminate lineages
a KG and are especially common in infant acute leukemias and secondary
IDH1 mut or IDH2 mut AML induced by Topo II inhibitors. An aminonucleoside DOT1L
221
2-HG inhibitor has entered clinical trials. It occupies the S-adenosyl-L-methi-
onine (SAMe) binding pocket of DOT1L and induces conformational
changes, thereby contributing to high-affinity binding and specificity of
DNA Histone Prolyl the inhibitor.
demethylases demethylases hydroxylases Preclinical data demonstrate nanomolar antiproliferative activity
Me specific for MLL-rearranged cell lines, and in a rat xenograft model of
Me EGLN1 MLL-rearranged leukemia, addition of the inhibitor led to complete
Me Me tumor regression. Based upon these preclinical data, the DOT1L inhib-
Me HIF1a itor has recently entered clinical trials in relapsed/refractory patients
with leukemia involving the translocation of the MLL gene at 11q23
(NCT01684150). 221
Hypermethylator Histone methylation, Astrocyte
phenotype in glioma, and inhibition transformation Enhancer of Zest Homologue 2 Inhibitors
and inhibition of of lineage
hematopoietic specific gene Enhancer of zest homologue 2 (EZH2) is the catalytic subunit of the
differentiation expression polycomb repressive complex 2 (PRC2), and methylates lysine K-27
on histone H3 as well as other nonhistone targets. Monoallelic point
Figure 22–6. Isocitrate dehydrogenase (IDH) mutations produce mutations in EZH2 lead to increased catalytic activity and hyperdim-
2-hydroxyglutarate (2HG), an inhibitor of demethylation reactions. ethylation or hypertrimethylation of H3K27 with concomitant tran-
The R-isomer of 2HG activates EGLN1 gene encoded enzymes, prolyl
hydroxylases, which, in turn, activate the ubiquitination and degrada- scriptional repression of DNA-damage response pathways in germinal
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tion of hypoxia inducible factors (HIFs). (Reproduced with permission from center diffuse large B-cell lymphoma and follicular lymphoma. The
Schulze A, Harris AL: How cancer metabolism is tuned for proliferation and Y641 residue is most commonly mutated with up to 22 percent of ger-
vulnerable to disruption. Nature 491(7424):364–373, 2012.) minal center diffuse large B-cell lymphoma and 10 percent of follicular

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