Page 1056 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 59 Clinical Manifestations and Treatment of Acute Myeloid Leukemia 939

Whether GO will return to the United States market is unknown. IDH Inhibitors
Yet, interest in anti-CD33–directed therapies persists. SGN–CD33A
is an anti-CD33 engineered cysteine antibody conjugated to an Somatic mutations in the metabolic enzymes IDH1 and IDH2 result
average of two molecules of a pyrrolobenzodiazepine dimer, a in accumulation of the oncometabolite R-2-hydroxyglutarate (2-HG).
highly potent DNA crosslinking agent. SGN-CD33A has shown High levels of 2-HG lead to epigenetic changes and impaired cellular
single-agent antileukemia activity, and combinations with stan- differentiation. Several compounds have been developed that specifi-
dard AML and MDS therapy are underway. AMG 330 is a novel cally target IDH1 R132H and IDH2 R140Q. Data from a phase I
CD33/CD3-directed bispecific T-cell engaging (BiTE) antibody. It study of AG-221, an oral, reversible, and selective inhibitor of IDH2,
+
is highly active against CD33 AML cell lines and can potently showed high levels of clinical activity with objective response rates
lyse leukemic blasts from AML patients. Clinical studies are in of 50%.
progress.
Inhibitors of Polo-Like Kinases
CPX-351
Polo-like kinases belong to a family of serine/threonine protein
CPX-351 is a liposomal formulation of cytarabine and daunorubicin kinases that play a key role in mitotic checkpoint regulation and
at a fixed 5 : 1 molar ratio within 100-nm bilamellar liposomes. This cell division. Volasertib is a low–molecular-weight, ATP-competitive
formulation allows delivery of a maximally synergistic drug ratio to kinase inhibitor that potently inhibits Polo-like kinases and has
tumor cells and may enhance treatment efficacy. In a phase II ran- shown in vivo efficacy in AML xenograft models. A randomized
domized study of CPX-351 versus 3 + 7 in older patients with phase II trial of low-dose cytarabine with or without volasertib
untreated AML, the investigational combination achieved signifi- in patients not suitable for intensive induction therapy (median
cantly higher remission rates than standard 3 + 7 and significantly age 75 years) showed higher rates of CR and significantly better
25
better OS in the subgroup with secondary AML. Final results of a EFS and OS with the addition of volasertib. The volasertib
randomized phase III study of CPX-351 versus standard 3 + 7 in arm was also associated with a higher frequency of adverse events
patients aged 60 to 75 years with high-risk (secondary) AML con- (mainly myelosuppression, neutropenic fever, and gastrointestinal
firmed the significant improvement in remission rate and median OS toxicities).
with CPX-351. Pending filing and FDA assessment of this com-
pound, CPX-351 may become a new standard of care for this patient
group. Other Novel Agents

Sapacitabine is an oral cytarabine analog whose cyano structure causes
FLT3 Inhibitors irreparable single-strand DNA breaks. It is active in AML and patients
with MDS, including those who have lost response to standard
Inhibitors of FLT3 have been in clinical trials for many years. Yet no HMAs.
FLT3 inhibitor has received FDA approval. The clinical activity of Guadecitabine (SGI-110) is a second-generation dinucleotide of
single-agent first generation inhibitors (midostaurin, lestaurtinib, decitabine and deoxyguanosine with prolonged half-life and activity
sunitinib, sorafenib, semaxanib, tandutinib) has been limited, only in AML and high-risk AML.
demonstrating transient reductions in blood and/or marrow blasts Signaling through the RAS/RAF/MEK pathway is activated in
but, for most, without achievement of objective responses. In a many cancers and has been one of the first targets for small-molecule
randomized study of standard salvage therapy versus addition of kinase inhibitors. Inhibitors of MEK1/2 have demonstrated clinical
lestaurtinib, no benefit with regard to response rate or survival was activity in the salvage therapy for AML. Of 39 patients with relapsed
observed. A randomized study of standard induction therapy in or secondary AML, a third responded in the presence of KRAS or
patients 18 to 60 years of age with or without sorafenib (regardless NRAS mutations compared with only 8% in the absence of
of FLT3 status) demonstrated superior relapse and event free survival mutations.
for the sorafenib treated group. The CALGB 10603 (RATIFY) study Inhibitors of DOT1L have shown activity in patients with MLL-
randomized 717 patients between ages 18 and 60 with newly diag- rearranged AML.
nosed FLT3 positive (both ITD and TKD) AML to receive a standard Other targets are BCL2 and MDM2 and other antiapoptotic
3 + 7 induction alone or in combination with midostaurin. Ten years proteins; nuclear export proteins; multidrug resistance proteins; the
after conception the final results were presented in 2016. Although ubiquitin–proteasome pathway; aurora kinases, which play an impor-
the addition of midostaurin did not improve remission rates, the tant role in the formation and organization of the mitotic spindle
FLT3 inhibitor group enjoyed a statistically significant event free and apparatus; the mammalian target of rapamycin/phosphatidylinositol
overall survival benefit that extended to both ITD and TKD groups 3-kinase/AKT pathway; components of the microenvironment
and persisted regardless of mutation load. The outcome of this study (e.g., CXC-chemokine receptor 4 and CXC-chemokine ligand 12
defines the combination of 3 + 7 and midostaurin (FDA approval inhibitors). Venetoclax is a recently approved BCLR inhibitor for the
pending) as a new standard of care for this patient population. treatment of chronic lymphocytic leukemia. Its activity in AML and
Higher single-agent activity (including objective remissions) has MDS is being evaluated in clinical studies.
been observed with the next generation FLT3 inhibitors quizartinib,
gilteritinib, and crenolanib. They are being actively evaluated in
combination with standard chemotherapy in various clinical trials in ACUTE PROMYELOCYTIC LEUKEMIA
frontline and relapsed FLT3 positive patients.
Various factors influence the activity of FLT3 inhibitors. Blasts APL is a rare subtype (approximately 10% of all AML diagnoses)
with a low mutant allelic burden of FLT3/ITD may be less dependent with unique pathophysiologic, clinical, and therapeutic features. The
on FLT3 signaling. Whether or not there is an association of the size median age at diagnosis of 40 years is younger than for other types
of the ITD fragment with outcome is controversial. Secretion of of AML; APL occurs more frequently in Hispanics and the obese. If
FLT3 ligand is another resistance mechanism under discussion. The diagnosed promptly and managed appropriately, APL has the most
spectrum of activity of most of the FLT3 inhibitors extends to other favorable prognosis of all AMLs. On the other hand, catastrophic
kinases so that there are differences with regard to specificity between bleeding events (coagulopathies, thrombocytopenia), differentiation
these agents. Next generation FLT3 inhibitors are more specific syndrome, or infectious complications can be associated with a high
towards FLT3 compared to other kinases than is observed in the first early mortality (in some reports 20–30%). In 80% of the cases, APL
generation compounds. cells are hypergranular with many Auer rods. A microgranular variant