Page 1428 - Williams Hematology ( PDFDrive )

1402 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1403

daunorubicin and cytarabine have entered trials. This has shown of patients with AML. Several small-molecule FLT3 tyrosine kinase
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some responses in older adults with secondary leukemia. inhibitors have been formulated, but none have yet received regula-
tory approval. 826–831 Myeloblast differentiation may occur, including a
Epigenetic Modulation syndrome with neutrophilic dermatosis wherein the neutrophils are
Methylation of DNA at critical sites can cause transcriptional inactiva- FLT3-positive. FLT3-mutant allelic burden may predict response
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tion of genes or chromosomal instability. In AML, aberrant methyla- to such inhibitors. These agents are in phase I and phase II trials,
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tion, especially preferential methylation of chromosome 11, has been in which they have induced a decline in blood blast cells, but rarely
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described. Epigenetic gene silencing caused by DNA methylation is result in complete remissions. 834,835 Newer-generation FLT3 inhib-
a target for presumptive demethylating agents such as 5-azacytidine or itors have been developed in an attempt to improve their effects.
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decitabine, and silencing mediated by histone deacetylation is a target Crenolanib may inhibit both ITD and TKD mutations. Quizartinib
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for histone deacetylases. Decitabine, a potent agent, can cause mat- (previously AC220) showed activity in a phase I study in relapsed/refrac-
uration and growth arrest of AML cells. 799–801 5-Azacytidine also has tory AML, especially in patients with FLT3-ITD mutations. Trials are
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activity in AML, and it is being studied in an oral formulation. These now under way to examine inhibitors such as midostaurin (PKC412)
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agents, singly or in combination, have resulted in response rates of 25 to and sorafenib in combination with cytostatic drugs for AML.
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60 percent. Methylome analysis may be useful as a pharmacodynamic Kit Tyrosine Kinase Inhibitors: Imatinib Mesylate Activation of
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end point in those treated with decitabine, and higher levels of miR- the KIT tyrosine kinase by somatic mutation has been documented in a
29b are associated with responses to decitabine. Histone deacetylase small minority of AML cases. Paracrine or autocrine activation of KIT
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inhibitors can restore retinoic acid-dependent transcriptional activation may occur in AML cells. Imatinib mesylate has induced a complete
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and maturation in AML blasts. Depsipeptide can promote histone remission in refractory secondary AML, but this is a very uncommon
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acetylation and gene transcription in RUNX1/ETO-positive leukemic result of its use. Dasatinib has been studied in CBF leukemias with
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808
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cells. Depsipeptide (romidepsin), LBH589, vorinostat (suberoy- a KIT mutation in conjunction with chemotherapy, but final results of
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lanilide hydroxamic acid [SAHA]), and MGCD0103 have each studies are awaited. 844
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811
been studied in early phase trials in leukemia. Combination therapy of Nuclear Factor-Kappa B Inhibitors AML leukemia stem cells
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these agents with other targeted therapies is being explored, and com- have activated NF-κB, unlike normal HSCs. Proteasome inhibitors
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bination therapy with hypomethylating agents and histone deacetylase such as bortezomib inhibit NF-κB and have been examined in AML.
inhibitors has been reported. 813 They have been found to increase sensitivity to chemotherapy agents in
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Inhibitors of DOT1L, Isocitric Dehydrogenase, and MDM2 NPM1-mutated AML. Bortezomib is also being combined with che-
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The histone methyltransferase DOT1L is necessary for sustaining motherapy agents in AML patients. Other inhibitors more specific to
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MLL-rearranged, AML. EPZ-5676, an aminonucleoside inhibitor of the NF-κB family have been proposed for study in AML.
DOT1L histone methyltransferase activity is under clinical investiga- Other Signal Transduction and Tyrosine Kinase Inhibitors
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tion in MLL-rearranged leukemias. Other DOLT1L inhibitors are Numerous inhibitors of activated tyrosine kinases have been examined
These include mammalian target of rapamycin
849,850
being explored in IDH1/2 mutated AML. AGI-6780 has been iden- for AML therapy. 851,852 853,854
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tified as an IDH2 R140Q inhibitor with potential for differentiation. (mTOR) inhibitors, phosphoinositol 3′-kinase inhibitors, AKT
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Inhibitors of MDM2, a regulator of p53 and p53-specific E3 ubiquitin inhibitors, such as perifosine, small-molecule mitogen-activated
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ligase have also entered trials. 817 protein kinase (MEK) kinase inhibitors, Aurora kinase inhibitors,
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and heat-shock protein inhibitors. None of these agents have had an
Antibodies to CD33 impact on AML survival as single agents, but using a combination of
The CD33 antigen is expressed on approximately 90 percent of AML agents that target multiple pathways or using multitargeted tyrosine
blasts and is a target for antibody-mediated destruction. Gemtuzumab kinase inhibitors may hold promise for incremental improvements in
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ozogamicin is a recombinant humanized anti-CD33 monoclonal AML therapy. There is some indication that extramedullary disease
immunoglobulin G antibody conjugated to the cytotoxin calicheami- may increase in incidence in cases treated with signal transduction
4
cin. The conjugated antibody is rapidly internalized and causes agents alone. 860
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subsequent cell apoptosis. Hyperbilirubinemia and transaminase Other Inhibitors of Signal Transduction and Apoptosis
819
elevations can occur. Although it results in similar survival rates as Pathways Many malignancies overexpress antiapoptotic proteins, such
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standard chemotherapy reinduction, its use was associated with fewer as BCL-2 and BCL-x . Small-molecule BCL-2 homology domain-3
L
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days of hospitalization. In patients who relapsed between 3 and 11 (BH3) mimetics such as ABT-737 and GX15–070 (obatoclax)
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months, gemtuzumab ozogamicin resulted in higher remission rates inhibit BCL-2. CDDO-Me, a triterpenoid, studied in vitro induces apop-
compared to regimens containing high-dose cytarabine in different tri- tosis and differentiation in AML cells through activation of caspase-8
als. However, in patients who had prolonged first remissions of greater and caspase-3 and induction of mitochondrial cytochrome c release. 864
than 19 months, cytarabine resulted in superior remission rates. Prior Prenylation Inhibitors: Farnesyltransferase inhibitors (FTIs) 865–868
821
gemtuzumab ozogamicin exposure may increase the risk of venoocclu- and geranylgeranyltransferase-1 inhibitors (GTIs), such as statins, have
sive disease in patients who later undergo myeloablative allogeneic HSC been examined as therapy in AML. Examples of responses of AML to
869
transplantation procedures. Gemtuzumab ozogamicin was approved lovastatin have been reported. Simvastatin adds to the effect of cyta-
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by the FDA in 2000, but withdrawn from the market in 2010. Studies in rabine’s inhibition of AML cell lines. Other studies suggest that the
Europe are examining its role in induction treatment coupled with stan- statins may mediate antileukemic effects independent of Ras/Rho pre-
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dard chemotherapy, in postremission therapy, and in the treatment of nylation through blockade of cholesterol responses to cellular injury.
APL. 823–825 In those studies, it did not alter remission rates but appeared Effectiveness of either FTIs or GTIs as single agents has been minimal
to decrease relapse rate or improve relapse-free survival. in untreated AML patients. 865–868
Maturation Therapies Several analogues of vitamin D inhibit
Therapies Targeted to Signal Transduction Mediators AML cells by inducing inhibition of cyclin-dependent kinases. In
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Tyrosine Kinase Inhibitors: FLT3 Inhibitors Constitutively activating general, AML cells have not responded to retinoids. Single-strand con-
FLT3 receptor mutations have been found in approximately 30 percent formational polymorphism analysis and DNA sequencing of leukemic
Kaushansky_chapter 88_p1373-1436.indd 1403 9/21/15 11:02 AM