Page 1083 - Hematology_ Basic Principles and Practice ( PDFDrive )

966 Part VII Hematologic Malignancies

the promoters of numerous tumor suppressor genes, including
Signal Transduction Inhibitors CDKN2A, CDKN2B, FHIT, SOCS1, CTNNA1, and others.
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Later, with the advent of genome-wide methylation profiling, it was
Activating mutations in receptor tyrosine kinases like NRAS and further observed that this aberrant methylation is often a global
FLT3 are relatively uncommon in MDS, not because they never occur phenomenon in MDS and that global hypermethylation, in particu-
in this population, but because they usually act as catalysts for pro- lar, appears to confer a poor prognosis. 488
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gression to secondary AML. The consideration for use of FLT3 This characterization of aberrant methylation in MDS soon led
inhibitors in MDS is similar to those in s-AML, and data are limited. to the identification of hypomethylating agents (HMA) as a candidate
A more thorough discussion of these agents may be found in Chapter class of MDS drugs. The prototypical hypomethylator, 5-azacytidine
59 (AML). (azacitidine), was synthesized in the 1960s and its hypomethylating
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activity first clearly characterized in 1980. It is an azo-substituted
pyrimidine analogue that incorporates into RNA and is from there
Other Agents converted to a deoxynucleotide and incorporated into DNA, where
it binds and irreversibly inhibits DNMT1. The in vitro result is a
A number of other agents have been used in MDS and reported either global decrease in cytosine methylation, which leads to differentiation
in anecdotes or small, nonrandomized series of patients. Historically, in some leukemia cell lines. Of note, azacitidine also appears to have
many patients with RARS were started on vitamin B 6 because of its nonepigenetic mechanisms of action, including some degree of direct
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efficacy in familial sideroblastic anemia, but it has shown little efficacy cytotoxicity and immune stimulation. Both azacitidine and the
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in adults. Other dietary supplements, include retinoids (vitamin A related compound decitabine (5-aza-2’-deoxycytidine) are now fre-
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analogues), vitamin D, and vitamin K2, have all been tried quently administered in both MDS and AML.
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because of favorable effects on differentiation in vitro, but have not Standard dosing of azacitidine is 75 mg/m administered subcu-
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been effective in humans. A number of other drugs have also been taneously once per day for 7 consecutive days each month. This
trialed in humans based on similar observations of prodifferentiation was the dosing schedule used in the first major study of hypometh-
effects in preclinical experiments, all without comparable efficacy in ylating agents in MDS, CALGB 9221, in which azacitidine was
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human patients. These include amifostine as a single agent, the found to be superior to best supportive care both in terms of quality
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solvent hexamethyl bisacetamide, and alpha and gamma interferon. of life and risk of progression to AML. In this study, about 60%
Interferon, in particular, has recently been shown to cause normal of patients had some degree of response to azacitidine, although
HSCs to exit quiescence in mouse models, 473,474 but whether it can consensus response criteria were not used. Most of these responses
be used for similar purposes to “prime” MDS stem cells for subse- were minor hematologic improvement, but about 15% of patients
quent treatment with cytotoxic therapy has not yet been explored. had a pathologic complete response. Most of those who responded
Given their efficacy in promyelocytic leukemia, both all-trans reti- did so within 6 months. There was a nonsignificant trend toward an
noic acid (ATRA) and ATO have been trialed in small numbers of improvement in overall survival with azacitidine, and side effects
MDS patients in a similar attempt to induce differentiation. ATO tended to be mild, including nausea and vomiting and transient
has shown responses in up to 20% of MDS patients in several small myelosuppression.
series, 475–478 but the molecular basis for this action and how to predict Based on these data and a large increase in requests for compas-
who will respond are unclear. ATRA by itself has largely been inef- sionate use of the drug after CALGB 9221 was first presented in
fective, likely caused by the absence of the PML-RARA fusion protein 2002, the Food and Drugs Administration (FDA) granted approval
that is the basis for its efficacy in acute promyelocytic leukemia to azacitidine for MDS in 2004. A subsequent study, AZA-001
(APML). 479,480 In vitro data suggest that in some AML models, comparing azacitidine 1 : 1 to the patient and doctor choice of either
downstream targets of the retinoic acid receptor may be epigenetically standard induction, low-dose cytarabine, and best supportive care in
silenced by abnormal induction of histone demethylases such as 358 patients with higher-risk MDS or CMML showed a median
LSD1, which can be inhibited by tranylcypromine, a monoamine 9-month improvement in overall survival for those treated with
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oxidase inhibitor (MAOI) approved in Europe to treat depression. azacitidine (24 versus 15 months). This represents the only major
In vitro, the combination of ATRA with tranylcypromine in non- study to date in which a survival benefit has been shown for a drug
APML leukemia derepresses targets of the retinoic acid receptor and in MDS. Other studies have shown that a more convenient 5-day
significantly impairs the ability of leukemia stem cells to engraft in azacitidine dosing schedule appears to be effective, but this has not
immunodeficient mice. Whether this pathway can be similarly been directly compared to the 7-day schedule, which remains the
reactivated in MDS, and whether this is a viable therapeutic combi- standard. One recent study suggested an improvement in response
nation in patients, also remain as yet unexplored. from prolonged administration of azacitidine, though all patients in
A number of other novel agents remain in clinical trials for lower- this study had higher rates of hematologic normalization compared
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risk MDS at the time of this writing. These include inhibitors of to historical controls, for unclear reasons. 494
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the transforming growth factor-beta receptor, inhibitors of toll-like The other major hypomethylating agent, decitabine (5-aza-2′-
receptors, chimeric antibodies to activin, mitochondrial modulators, deoxycytidine), is also FDA-approved for treatment in all subclasses
RAS pathway inhibitors, and anti-CD33 molecules. In addition, of MDS. Although structurally similar to azacitidine, decitabine has
there are ongoing trials evaluating combinations of existing therapies, a deoxyribose backbone that permits it to be directly incorporated
including hypomethylating agents, histone deacetylase (HDAC) into DNA. At higher doses it introduces DNA cross-linking and
inhibitors, lenalidomide, and hematopoietic growth factors. While cell-cycle arrest, a mechanism more akin to a cytotoxic agent, but at
some of these trials may identify novel therapies or combinations with lower doses it appears to primarily act as a hypomethylating agent. 495
efficacy for subsets of MDS patients, whether any of them will have Similar to azacitidine, decitabine has been shown to improve
substantial impact on the treatment landscape for low-risk MDS outcomes for patients with MDS, including a reduced transfusion
remains to be seen. requirement and slower transformation to AML. It may induce
responses more quickly than azacitidine; for instance, in the multi-
Higher-Risk Disease center ADOPT (alternative dosing of decitabine for outpatient
therapy) study, 90% of patients responded after four cycles, rather
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than the six cycles seen in the largest azacitidine trials.
Hypomethylating Agents In contrast to azacitidine, however, decitabine has never been shown
to confer an overall survival benefit. Some of the difference in out-
MDS genomes frequently display aberrant methylation patterns rela- comes may be explained by difficulties establishing the optimal dose
tive to normal hematopoietic cells. This observation was initially and schedule; in the earliest trials it was administered at a dose of
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made in the 1990s, when investigators noted hypermethylation in 15 mg/m given IV every 8 hours for 3 days, but subsequent