Page 1385 - Williams Hematology ( PDFDrive )

1360 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1361

There are anecdotes of hematopoietic responses to vitamin K methyltransferase 1, reduces cytosine methylation, and induces matura-
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(menatetrenone), for unclear reasons. 467,468 Glucocorticoids, vitamin A tion of some leukemic cell lines. In addition to epigenetic changes, azac-
analogues (retinoids), vitamin D analogues such as dihydroxyvitamin itidine also is an antiproliferative drug, alters NF-κB and other signaling
D , the polar-planar solvent hexamethylene bisacetamide, the antioxi- pathways, alters expression of cell-surface antigenic epitopes that can
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dant amifostine, and interferon are among other agents that can induce stimulate a regulatory T-cell immunologic response, and retains some
in vitro maturation of mouse and human leukemic cells but have limited cytotoxic activity akin to low-dose cytarabine as measured by induction
clinical activity. 469–471 Glucocorticoids can induce neutrophil increment of γH2AX (a marker of DNA strand breaks). 496–499 Administration of the
via demargination, but this does not prevent infections and there is drug and its congener decitabine has resulted in improvement of some
at least some reason for concern about increased risk of fungal infec- patient’s MDS, and these agents are also active in AML. 500–502
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tions. 472,473 Use of cis-retinoic acid, isotretinoin, or all-trans-retinoic acid Azacitidine is typically administered at a dose of 75 mg/m once
(ATRA) has produced only slight, transient (few weeks) improvement per day given subcutaneously for 7 consecutive days each month. In a
in a very small proportion of patients with oligoblastic leukemia. 474,475 cooperative group randomized study conducted in the 1990s (Cancer
Arsenic trioxide, used as a single agent or in combination with and Leukemia Group B [CALGB] 9221), azacitidine was superior to
other therapies, results in responses in up to 20 percent of cases. 472,476–478 supportive care in terms of hematopoietic improvement and AML pro-
Lower-risk MDS patients were most likely to show benefit in one arse- gression. Quality of life was also enhanced. 323,503 Complete responses
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nic study. The mechanism of action of arsenic in MDS is unclear. were seen in approximately 15 percent of azacitidine-treated patients,
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Bortezomib, a proteasome inhibitor that indirectly targets NF-κB, and nearly 50 percent of patients had hematologic improvement, reduc-
has limited activity in MDS as a single agent but might be useful in tion of blasts, decrease in abnormal metaphases on cytogenetic analysis,
combination. 480–482 The AKT/mTOR (mammalian target of rapamy- or some combination of those changes. Ninety percent of responses
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cin) pathway is active in MDS, but there are no data on treatment with were seen by cycle six of therapy, although a few patients responded to
mTOR inhibitors. 483,484 further cycles beyond six. In another series, subclasses of MDS did
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For those patients who are unlikely to respond to the therapies not predict for response to azacitidine therapy. Consequently, azaciti-
described above or for those for whom such treatments have been dine was approved by the FDA in 2004 for treatment of all FAB subtypes
attempted and failed, treatments more commonly used for higher-risk of MDS.
MDS such as azacitidine or decitabine can be used. In those not respond- In a randomized multicenter study of higher-risk MDS patients
ing to these approved agents, AHSCT or other investigational options where azacitidine was compared to the physician’s choice of one of three
can be considered (see below). conventional care regimens that included supportive care, low-dose
A number of novel agents are currently undergoing clinical trials cytarabine treatment, or intensive induction chemotherapy, azacitidine
for patients with lower risk MDS for whom ESAs and other agents have increased survival by a median of 9 months compared to standard care
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failed. For instance, a multicenter trial of sotatercept, a soluble activin regimens (24 vs. 15 months). This was the first agent shown in a ran-
receptor type 2A immunoglobulin (Ig) G-Fc fusion protein that acts domized fashion to extend survival in MDS.
as a ligand trap for members of the transforming growth factor beta Treatment with azacitidine can usually be accomplished on an
(TGF-β) superfamily, is ongoing in MDS. The dual p38 mito- outpatient basis, and the efficacy of intravenous administration seems
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gen-activated protein (MAP) kinase/Tie2 kinase inhibitor Arry-614 to be similar to that with subcutaneous drug delivery. An oral for-
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was associated with hematologic improvements in patients for whom mulation of azacitidine is being studied. Other schedules of adminis-
hypomethylating agents have failed yet who still meet IPSS criteria for tration to accommodate outpatient therapy have been reported to have
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lower-risk disease. Although activating kinase mutations are rare in benefit but have not been directly compared to the 75 mg/m daily dose
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MDS and kinase inhibitors such as imatinib have not shown efficacy for 7 days every 4 weeks. Adverse events associated with azacitidine
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in MDS with the exception of the rare CMML-like syndrome associ- include treatment-emergent cytopenias, skin rash, injection site sore-
ated with t(5;12) and translocation of a gene encoding platelet-derived ness (which may respond to evening primrose oil ), mucositis, renal
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growth factor, 487,488 several other kinase inhibitors besides Arry-614 are insufficiency (uncommon), and gastrointestinal upset.
also being studied. The glutathione analogue TLK199 (ezatiostat hydro- 5-Aza-2′-deoxycytidine (decitabine) is also FDA approved for all
chloride [Telintra]) had some activity in lower-risk MDS and restored MDS risk categories. Although also a 5-azo–substituted pyrimidine
sensitivity to lenalidomide in some patients who had lost response, but nucleoside analogue that inhibits DNA methyltransferase, decitabine
development of this agent appears to have been abandoned. 489–491 differs from azacitidine in that it is primarily incorporated into DNA,
has a distinct profile of sensitive cell lines among the NCI-60 panel com-
THERAPY FOR PATIENTS WITH pared to azacitidine (more similar to cytarabine), and may work faster.
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HIGHER-RISK DISEASE In one study, 90 percent of patients had responded by the end of cycle
four of decitabine therapy, compared to cycle six with azacitidine, but
Hypomethylating Agents (DNA Methyltransferase Inhibitors): this was a cross-study comparison and not randomization. Seventeen
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Azacitidine and Decitabine percent of patients in one series had a major cytogenetic response on an
Recognition of the high prevalence of DNA cytosine methylation intention-to-treat basis after a median of three courses. The median
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abnormalities in MDS, including hypermethylation and consequent duration of cytogenetic response was 7.5 months in all IPSS groups.
silencing of expression of tumor-suppressor genes, contributed to clin- Patients who responded had improved survival compared with patients
ical development of DNA hypomethylating agents. 492,493 Another factor in whom the cytogenetically abnormal clone persisted. While decita-
in development of these agents was the detection in vitro of the potential bine was initially developed using a 3-day, nine-dose inpatient sched-
for DNA hypomethylating agents to induce differentiation of immature ule, a 5-day intravenous administration schedule for outpatient use was
hematopoietic cells, including neoplastically transformed cells. 388,494,495 found to be optimal in one series, which compared several doses and
5-Azacytidine (azacitidine) is an azo-substituted pyrimidine ana- schedules; examination of optimal doses and schedules continues. 516–518
logue that is primarily incorporated into RNA. It can be converted to Decitabine also has cytotoxic activity like cytarabine, but may work at
a deoxynucleotide by ribonucleotide reductase and incorporated into least partly through demethylation, as it has resulted in demethylation
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DNA where it binds to and irreversibly inhibits the enzyme DNA of a hypermethylated INK4B gene in patients. Treatment-emergent

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