Page 981 - Hematology_ Basic Principles and Practice ( PDFDrive )

864 Part VII Hematologic Malignancies

PI3K Inhibitors studies have demonstrated activity of afuresertib when used in
Idelalisib (CAL-101, GS 1101) is a highly selective inhibitor of the combination with bortezomib and dexamethasone for the treatment
p110d isoform of PI3K (PI3Kδ), an isoform of PI3K that is expressed of myeloma, and with ofatumumab for the treatment of CLL. Fre-
selectively in hematopoietic cells, in particular those of the lymphoid quent adverse events include gastrointestinal complaints (diarrhea,
lineage. Idelalisib has in vitro activity against lymphoid cell lines and nausea, dyspepsia, gastrointestinal reflux, and anorexia) and fatigue.
primary CLL and MCL cells, but does not affect normal B-cell viabil- Severe adverse events include rash, fatigue, elevations in liver function
ity (see Chapter 77). Idelalisib inhibits not only the B-cell receptor tests, and thrombocytopenia.
signaling pathway-induced survival signals but also appears to disrupt
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the effects of microenvironmental signals on neoplastic cells, affect- Inhibitors of the Mammalian Target of Rapamycin
ing chemotaxis of tumor cells, which could explain the transient The first mTOR inhibitor discovered was the naturally occurring mac-
lymphocytosis observed after treatment of CLL patients with this rolide rapamycin (sirolimus), widely used as an immunosuppressant
agent. Clinical trials have shown that idelalisib is active in treating (see Chapter 108). The importance of the mTOR pathway in cancer
patients with relapsed CLL and other relapsed indolent lymphoid suggested this agent would have antineoplastic activity. Improvements
malignancies. Additional trials are investigating the activity of idelal- in solubility and pharmacokinetic properties led to development of
isib in combination with other chemotherapeutic agents for the rapamycin analogs (rapalogs), of which everolimus and temsirolimus
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treatment of aggressive and indolent lymphoid malignancies, as well are available as antineoplastic agents. The mechanism of rapamycin
as its role in the treatment of AML and ALL. and its analogs is similar: after complexing with the small protein
Idelalisib is currently approved as a single agent for relapsed fol- FKBP12, they bind irreversibly to the FKBP12-rapamycin binding
licular lymphoma and SLL and in combination with rituximab for site on the mTOR protein. Acute rapamycin treatment only affects
CLL patients. The approved dosing is 150 mg PO twice daily. mTORC1 because the FKBP12-rapamycin is occluded in mTORC2.
Common dose-limiting toxicities include diarrhea, fever, and rash. Prolonged rapalog exposure may result in decreased mTOR avail-
Elevation of liver function tests is also commonly observed, requiring ability and therefore indirectly decreased mTORC2 activity through
interruption of idelalisib. Serious adverse events include hepatotoxic- limited mTORC2 complex formation. It is well recognized that
ity occurring in the first 3 months of treatment, diarrhea and colitis, growth factor signaling initiated through the receptor tyrosine kinases
intestinal perforation, pneumonitis, and neutropenia. (RTKs) or caused by the activity of cytosolic tyrosine kinases (TKs),
such as BCR-ABL, results in activation of PI3K/AKT signaling.
Other PI3K Inhibitors AKT has been shown to phosphorylate and inactivate tuberous
Several other PI3K inhibitors are currently in various stages of sclerosis (TSC)2 (also known as tuberin), thereby disrupting its
development. Buparlisib is a pan PI3K inhibitor that appears to have interaction with TSC1 (or hamartin; see Fig. 57.6). Inhibition of the
activity against solid tumors as well as lymphoid malignancies. Pic- TSC1–TSC2 complex derepresses RHEB, which is a small G protein
tilisib is a PI3Kα and -δ selective inhibitor that may overcome that activates mTOR. When RHEB is in an active GTP-bound
resistance conferred by constitutive expression of the α isoform of state, its localization to the membrane stimulates mTOR-mediated
the enzyme. The main additional toxicity observed with PI3K inhibi- phosphorylation of the downstream eukaryotic initiation 4E-BP and
tors that target the α isoform is the development of insulin resistance ribosomal protein S6K1 (see Fig. 57.6). However, the association
and hyperglycemia. Additional agents have specificities that include of mTOR with the 150-kDa Raptor (regulatory-associated protein
other isoforms such as PI3Kβ, -δ and -γ. of mTOR) is necessary for the phosphorylation of 4E-BP and S6K1.
Resistance to selective PI3K inhibitors may be mediated by con- mTOR-mediated phosphorylation and activation of S6K1 results
stitutive activation of other isoforms of PI3K, as has been observed in the phosphorylation of the ribosomal S6 protein and eIF4B (see
in certain MCL lines and primary cells. O-linked N-acetylglucosamine Fig. 57.6). AKT has also been shown to directly activate S6K1.
transferase, dendrin, and PAK1 overexpression have been associated S6K1 activity is involved in regulating the translation of a group of
with resistance to idelalisib in cell lines. Mechanisms of resistance mRNAs that have a highly structured 5′-UTR (untranslated region),
may include PTEN loss, MYC and eIF4e upregulation. Mutations including mRNAs that have a 5′-TOP (terminal oligopyrimidines; a
of the catalytic domain of the α subunit (PIK3CA), common in solid stretch of 4–14 pyrimidines). 8
tumors, are much less frequent in hematologic malignancies, although The rapalogs temsirolimus and everolimus have been tested in
treatment with these agents may increase the selective pressure for lymphoid malignancies, and as single agents they have demonstrated
emergence of this abnormality. activity, although modest, against a variety of lymphomas (see Chapter
82). In the initial phase II study in patients with MCL, temsirolimus
AKT Inhibitors was administered at a dose of 250 mg based on a phase II study done
The frequent presence of AKT abnormalities in human neoplasms in renal cell carcinoma patients. A modest response rate was noted
makes this enzyme an attractive target for potential novel treatment (overall response rate [ORR]: 38%), but the majority of patients
strategies. Several drugs have been developed using dephosphoryla- required a dose reduction because of myelosuppression, particularly
tion of the active enzyme, allosteric enzyme inhibition, and ATP thrombocytopenia. A second trial in relapsed refractory MCL patients
competition as strategies for targeting AKT. Allosteric inhibitors bind was conducted to determine if a lower dose of temsirolimus could
the lipid-binding domain of AKT, resulting in a change in conforma- be used. In a follow-up phase II study, temsirolimus was given at
tion that prevents localization to the plasma membrane and subse- a dose of 25 mg IV weekly and was found to be as effective as the
quent activation. The allosteric inhibitor perifostine had modest 250-mg IV dose, with a modest improvement in the toxicity profile
clinical activity as a single agent in patients with Waldenström and dose reductions. This dose and schedule were also noted to be
macroglobulinemia and in patients with myeloma alone or in com- efficacious in nonmantle cell NHL, with thrombocytopenia being
bination with bortezomib. Phase III studies failed to demonstrate the main dose-limiting toxicity. A recent phase III study in relapsed
clinical benefit. MK2206 is another oral allosteric inhibitor with refractory MCL patients evaluated two different dosing regimens of
minimal single-agent activity against solid tumors and hematologic temsirolimus; 175 mg weekly for 3 weeks followed by 75 mg weekly
malignancies. versus 175 mg weekly for 3 weeks followed by 25 mg weekly versus
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Early ATP-competitive AKT inhibitors had significant off-target the investigator’s choice. At the conclusion of this study, it was
effects. More recently, ipatasertib (GDC-0068), an oral pan AKT determined that the temsirolimus regimen with 175/75 mg dosing
inhibitor, has been observed to have significant selectivity for AKT. had a significant improvement in progression-free survival (PFS)
Clinical development has focused on solid tumors. Afuresertib (GSK and objective response rate compared with the investigator’s choice.
2110183) is a reversible ATP-competitive AKT inhibitor with in Everolimus, given orally at a daily dose of 10 mg has single-agent
vitro activity against ALL, CLL, lymphoma, and myeloma. A phase activity against Hodgkin lymphoma (PMI, Waldenström macro-
I study of single-agent afuresertib showed activity in MM, with a globulinemia, diffuse large B-cell lymphoma [DLBCL], CLL, and
maximum tolerated dose of 125 mg PO once daily. Subsequent other relapsed lymphomas).