Page 1125 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 62 Acute Myeloid Leukemia in Children 991

AML therapy, target validation is slow and new therapeutic strategies
BOX 62.2 Prophylactic Antimicrobials
are needed.
As a result of prolonged periods of neutropenia secondary to myelosup-
pressive therapy, patients with acute myeloid leukemia (AML) are at
high risk of bacterial and fungal infections. Prior to our implementation Epigenetic Agents
of prophylactic antibiotics 10 years ago, we observed documented
bacterial infections, most commonly caused by viridans group strepto- Abnormal regulation of epigenetic modification, such as histone
cocci, in approximately two-thirds of AML patients. We subsequently acetylation and DNA methylation, is likely a key factor in the
demonstrated that the use of prophylactic antibiotics, such as cefepime pathogenesis of AML. A central role for epigenetic dysfunction in
alone or the combination of vancomycin and ciprofloxacin, dramatically AML is supported by the observation of mutations and transloca-
reduced the incidence of bacterial infection, decreased length of tions in genes involved in these processes, such as TET2, DNMT3,
hospital stays, and could be safely administered by caregivers in the
outpatient setting. Although the emergence of drug-resistant bacteria IDH1, IDH2, and MLL. These findings suggest that histone
is a concern, we believe that the benefits of prophylactic antibiotics deacetylase inhibitors and demethylating agents may be active, either
outweigh this potential risk. To further address the risks and benefits alone or in combination with chemotherapy, in AML. The histone
of prophylactic antibiotics, the Children’s Oncology Group is currently deacetylase inhibitor vorinostat as well as the DNA hypomethylating
evaluating prophylactic levofloxacin in children with leukemia who are agents decitabine and 5-azacytidine have shown promising activity
at high risk of infection. Because disseminated fungal infections are and are currently being tested in combination with chemotherapy. A
also common in children with AML, we recommend that all patients related epigenetic target in childhood AML is the DOT1L histone
receive antifungal prophylaxis with micafungin, caspofungin, voricon- methyltransferase, which is required for transformation by MLL
azole, or posaconazole. Micafungin and caspofungin provide excellent fusion proteins. A DOT1L inhibitor (EPZ-5676) is now in phase I
coverage for infections caused by Candida species, but are less active
than voriconazole and posaconazole against Aspergillus species. Our trials for adults and children with relapsed MLL-rearranged leuke-
use of prophylactic voriconazole has been associated with a decrease mia. Recently, the bromodomain and extraterminal (BET) family of
in the incidence of Aspergillus infections, but we have seen the emer- proteins (BRD2, BRD3, BRD4, and BRDT), which bind acetylated
gence of other molds, such as Fusarium, Mucor, and Rhizopus. lysines in histone tails and regulate gene expression by recruiting
Although we have successfully treated these infections with posacon- multiprotein complexes such as MLL to super enhancer regions,
azole, we must be wary of the development of posaconazole have also been explored as drug targets in AML. Preclinical models
resistance. show that BET inhibitors are active against a variety of malignan-
cies, including AML, and at least four such inhibitors are in early
clinical trials.

Disseminated fungal infections, most commonly caused by
Candida and Aspergillus species, are also frequently seen in children Antibody-Based Therapies
with AML. Because several randomized, controlled trials demon-
strated the benefits of prophylactic antifungal therapy in adults with Most antibody-directed therapies for AML have focused on CD33,
cancer, many pediatric oncologists recommend antifungal prophylaxis which is expressed on the surface of leukemia blasts in greater than
for children with AML. Available agents include fluconazole, itracon- 90% of cases. GO, a humanized anti-CD33 antibody conjugated to
azole, voriconazole, posaconazole, micafungin, and caspofungin. calicheamicin, was approved by the United States Food and Drug
Among the azoles, fluconazole and itraconazole are not ideal because Administration in 2000, but was later withdrawn from the market
they are less active against Aspergillus species than voriconazole and because of concerns of toxicity. However, the results of randomized
posaconazole. Although the latter agents are both active against trials that were completed after the withdrawal of GO suggest that
Aspergillus species, posaconazole has greater activity against other the addition of GO to conventional chemotherapy reduces the risk
molds, such as Fusarium, Mucor, and Rhizopus. Micafungin and of relapse and improves event-free survival. Metaanalyses demonstrate
caspofungin are not as broadly active as voriconazole and posacon- that the benefit of GO was greatest among low-risk patients, with
azole, but their ease of administration (daily intravenous infusion), only modest benefits seen in intermediate-risk patients and no ben-
compatibility with other drugs, and less variable pharmacokinetic efits in patients with high-risk disease. Recently, a novel anti-CD33
properties suggest that they are reasonable choices as well. conjugate (SGN-CD33A), in which calicheamicin is replaced with a
synthetic pyrrolobenzodiazepine, was shown to be more potent than
GO at inducing apoptosis in AML in preclinical models, and is now
FUTURE DIRECTIONS being evaluated in Phase I clinical trials.
An alternative approach to enhancing the efficacy of CD33-
Tyrosine Kinase Inhibitors directed therapy is through the development of CD33/CD3-directed
bispecific T-cell engager (BiTE) antibodies. By bridging CD33 with
AML cells commonly possess aberrant receptor tyrosine kinase activ- T-cell receptors (TCRs), BiTE antibodies can direct T-cell effector
ity as a result of genetic alterations, such as FLT3-ITD. These altera- functions to AML cells. In preclinical models, the CD33/CD3 BiTE
tions are seen in approximately 15% of pediatric and 30% of adult AMG 330 was able to recruit T cells, resulting in potent CD33-
AML cases, and are associated with a poor outcome, particularly in dependent cytotoxicity. Analogous to BiTE antibodies, bispecific
cases with high ratios of FLT3-ITD to wild-type FLT3. Evidence that killer cell engagers (BiKE) target CD16 on natural killer (NK) cells
FLT3 mutations are driver lesions suggests that they are rational and tumor-specific antigens, such as CD33. A CD33/CD16 BiKE
targets to which inhibitors should be tested. Recent studies have has recently been shown to induce NK cell function and eliminate
+
demonstrated that sorafenib, sunitinib, and other FLT3 inhibitors are CD33 AML cells in preclinical models. It is likely that BiTE and
highly active in patients with FLT3 mutations, but that prolonged BiKE antibodies will soon be tested in clinical trials for patients with
use of these agents is associated with the development of resistance, relapsed AML (Box 62.3).
most commonly caused by the acquisition of point mutations in the
kinase domain. Crenolanib, a novel tyrosine kinase inhibitor, is active
in sorafenib-resistant AML mouse models that contain the FLT3 Natural Killer Cell Therapy
D835 or F691 mutations, suggesting that this agent may extend
clinical benefit. Further studies are needed to determine the optimal The beneficial effects of KIR-mismatched donor NK cells in the
dose, schedule, and combination of inhibitors that are required to setting of allogeneic HSCT for AML has led to interest in the use
improve the long-term outcome of patients with FLT3 mutations. of allogeneic NK cells in the non-HSCT setting. We performed a
Although tyrosine kinase inhibitors represent a distinct approach to pilot study that demonstrated that infusions of haploidentical NK